Primary carboxamides as btk inhibitors

ABSTRACT

The invention provides compounds of Formula (I) 
     
       
         
         
             
             
         
       
     
     pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/421,006, filed on May 23, 2019, which is continuation of U.S. patentapplication Ser. No. 15/398,978, filed on Jan. 5, 2017, which iscontinuation of U.S. patent application Ser. No. 14/315,504, filed onJun. 26, 2014, now U.S. Pat. No. 9,567,339, which claims the benefit ofthe filing date, under 35 U.S.C. § 119(e), of U.S. ProvisionalApplication No. 61/839,729, filed on Jun. 26, 2013, and of U.S.Provisional Application No. 61/897,577, filed on Oct. 30, 2013, theentire content of each of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

The protein kinases represent a large family of proteins that play acentral role in the regulation of a wide variety of cellular processesand maintenance of cellular function. A partial, non-limiting, list ofthese kinases include: non-receptor tyrosine kinases such as the Tecfamily (BTK, ITK, Tec, ETK/BMX & RLK/TXK), Janus kinase family (Jak1,Jak2, Jak3 and Tyk2); the fusion kinases, such as BCR-Abl, focaladhesion kinase (FAK), Fes, Lek and Syk; receptor tyrosine kinases suchas epidermal growth factor receptor (EGFR), the platelet-derived growthfactor receptor kinase (PDGF-R), the receptor kinase for stem cellfactor, c-kit, the hepatocyte growth factor receptor, c-Met, and thefibroblast growth factor receptor, FGFR3; and serine/threonine kinasessuch as b-RAF, mitogen-activated protein kinases (e.g., MKK6) andSAPK2β. Aberrant kinase activity has been observed in many diseasestates including benign and malignant proliferative disorders as well asdiseases resulting from inappropriate activation of the immune andnervous systems. The novel compounds of this invention inhibit theactivity of one or more protein kinases and are, therefore, expected tobe useful in the treatment of kinase-mediated diseases.

Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase with akey role in immunoreceptor signaling (BCR, FcR, FcγR, DAP12, Dectin-1,GPVI, etc.) in a host of hematopoietic cells including B cells,platelets, mast cells, basophils, eosinophils, macrophages andneutrophils as well as osteoclasts involved in bone destruction (forreviews, see Brunner et al., 2005 Histol. Histopathol., 20:945, Mohamedet al., 2009 Immunol. Rev., 228:58). Mutations in BTK are known to leadto X-linked agammaglobulinemia (XLA) in humans and X-linkedimmunodeficiency (Xid) in mice, which are characterized by limitedB-cell production & reduced antibody titers (Lindvall et al., 2005Immunol. Rev., 203:200). The combined action of BTK in multiple celltypes makes it an attractive target for autoimmune disease. BTK isrelated with sequence homology to other Tec family kinases (ITK, Tec,ETK/BMX & RLK/TXK).

In B-lymphocytes, BTK is required for B-cell development and for Ca²⁺mobilization following of B-cell receptor (BCR) engagement (Khan et al.,1995 Immunity 3:283; Genevier et al., 1997 Clin. Exp. Immun., 110:286)where it is believed to downstream of Src family kinases (such as Lyn),Syk & PI3K. BTK has been shown to be important for both thymus-dependentand thymus-independent type 2 responses to antigens (Khan et al.,Immunity 1995, 3:283). In mast cells, studies using BTK mouse knock-outs(Hata et al., 1998 J. Exp. Med., 187:1235; Schmidt et al., 2009 Eur. JImmun., 39:3228) indicate a role for BTK in FcsRI induced signaling,histamine release & production of cytokines such as TNF, IL-2, & IL-4.In platelets, BTK is important for signaling through the glycoprotein VI(GPVI) receptor that responds to collagen and has been shown to promoteplatelet aggregation and contribute to cytokine production fromfibroblast-like synoviocytes (Hsu et al., 2013 Immun. Letters, 150:97).In monocytes and macrophages, the action of BTK in invoked in FcγRIinduced signaling and may also have role in Toll-Like Receptor-inducedcytokine responses including TLR2, TLR4, TLR8 & TLR9 (Horwood et al.,2003 J. Exp. Med., 197:1603; Horwood et al., 2006 J. Immunol., 176:3635;Perez de Diego et al., 2006 Allerg. Clin. Imm., 117:1462; Doyle et al.,2007 J. Biol. Chem., 282:36959, Hasan et al., 2007 Immunology, 123:239;Sochorava et al., 2007 Blood, 109:2553; Lee et al., 2008, J. Biol.Chem., 283:11189).

Therefore, inhibition of BTK is expected to intervene at severalcritical junctions of the inflammatory reactions resulting in aneffective suppression of autoimmune response. As such diseases involvingB-cell receptor activation, antibody-Fc receptor interactions & GPVIreceptor signaling may be modulated by treatment with BTK inhibitors.BTK inhibition is likely to act on both the initiation of autoimmunedisease by blocking BCR signaling and the effector phase by abrogationof FcR signaling on macrophages, neutrophils, basophils, and mast cells.Furthermore, blocking BTK would provide additional benefit viainhibition of osteoclast maturation and therefore attenuate the boneerosions & overall joint destruction associated with rheumatoidarthritis. Inhibiting BTK may be useful in treating a host ofinflammatory and allergic diseases—for example (but not limited to),rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiplesclerosis (MS) and type I hypersensitivity reactions such as allergicrhinitis, allergic conjunctivitis, atopic dermatitis, allergic asthmaand systemic anaphylaxis. For a review on targeting BTK as a treatmentfor inflammatory disorders and autoimmunity as well as leukemias andlymphomas, see Uckun & Qazi, 2010 Expert Opin. Ther. Pat., 20:1457.Because BTK is highly expressed in cancers of the hematopoietic system &BTK-dependent signaling in believed to be disregulated there, BTKinhibitors are expected to be useful treatments for B-celllymphomas/leukemias & other oncologic disease—for example (but notlimited to) acute lymphoblastic leukemia (ALL), chronic lymphocyticleukemia (CLL), non-Hodgkin's lymphoma (NHL), small lymphocytic lymphoma(SLL), and acute myeloid leukemia (for review, see Buggy & Elias 2012Int. Rev. Immunol. 31:119). Taken together, BTK inhibitors provide astrong method to treat a host of inflammatory diseases and immunologicaldisorders as well as hematologic cancers.

SUMMARY OF THE INVENTION

In a first embodiment the invention provides a compound of Formula (I):

or a pharmaceutically acceptable salt, pro-drug, biologically activemetabolite, isomer, or stereoisomer thereof, wherein:

-   -   X is NR² or S;    -   Y is N or CR¹, and Z is N or CR¹; or, Y is CR¹R² and Z is CR¹R²;    -   A is N or CR⁴;    -   E is N or CR⁵;    -   R¹ is independently H, deuterium, CN, halogen, CF₃,        —NR^(c)R^(c), —N(R^(a))C(O)R^(b), optionally substituted        (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl, optionally        substituted aryl, optionally substituted (C₃-C₆)cycloalkyl,        optionally substituted (C₃-C₆)cycloalkenyl, optionally        substituted heteroaryl, or optionally substituted saturated or        partially saturated heterocyclyl;    -   R² is independently H, deuterium, or optionally substituted        (C₁-C₃)alkyl;    -   R³ is halogen, —N(R^(a))₂, optionally substituted aryl,        optionally substituted (C₃-C₇)cycloalkyl, optionally substituted        saturated or partially saturated heterocyclyl, or optionally        substituted heteroaryl; or    -   R³ is —R³⁰¹-L-R³⁰² wherein        -   R³⁰¹ is a bond, —O—, —OCH₂—, —NR^(d)—, or optionally            substituted (C₁-C₃)alkylene, and        -   L is optionally substituted phenyl, optionally substituted            (C₃-C₆)cycloalkyl, optionally substituted heteroaryl or a            saturated or partially saturated heterocyclyl containing one            or more heteroatoms, at least one of which is nitrogen; or        -   L is -L¹-L² wherein L¹ is attached to R³⁰¹ and            -   L¹ is optionally substituted phenyl, optionally                substituted heteroaryl or optionally substituted                saturated or partially saturated carbocycle or a                saturated or partially saturated heterocyclyl; and            -   L² is a bond, CH₂, NR, CH₂N(H), S(O)₂N(H), or —O—;        -   R³⁰² is CN, —CH₂CN, optionally substituted —C(═)R^(302a),            —(CH₂)_(n)-optionally substituted saturated or partly            saturated heterocyclyl or optionally substituted            —S(O)₂(C₂)alkenyl;        -   wherein R^(302a) is optionally substituted (C₁-C₄)alkyl,            optionally substituted (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,            —C(O)—(C₁-C₄)alkyl, optionally substituted saturated or            partially unsaturated (C₃-C₆)cycloalkyl, optionally            substituted aryl, optionally substituted heteroaryl, —N(H)—            optionally substituted heteroaryl or —(CH₂)_(n)-optionally            substituted unsaturated or partly saturated heterocyclyl;    -   R⁴ is H, deuterium, CN, optionally substituted (C₁-C₃)alkyl,        optionally substituted (C₃-C₆) cycloalkyl or optionally        substituted saturated or partially saturated heterocyclyl, or        optionally substituted heteroaryl;        -   wherein the optionally substituted saturated or partially            saturated heterocyclyl; and optionally substituted            heteroaryl contain at least one nitrogen atom; or    -   R³ and R⁴, together with the carbon atoms to which they are        attached, form an optionally substituted, saturated, unsaturated        or partially unsaturated 5 or 6 membered carbocyclic ring or an        optionally substituted, saturated, or partially unsaturated 5 or        6 membered heterocyclic ring containing one or more heteroatoms        selected from N, S and O;    -   R⁵ is H, deuterium, halogen, or optionally substituted        (C₁-C₃)alkyl;    -   R^(a) is independently selected from H, —C(O)-optionally        substituted (C₂-C₆)alkenyl, optionally substituted (C₁-C₆)alkyl,        —(CH₂)_(n)-optionally substituted (C₃-C₆)cycloalkyl,        —(CH₂)_(n)-optionally substituted heterocyclyl, or        —(CH₂)_(n)-optionally substituted heteroaryl;    -   R^(b) is H, optionally substituted (C₁-C₆)alkyl, optionally        substituted (C₂-C₆)alkenyl, optionally substituted        (C₂-C₆)alkynyl, —CH₂—O-optionally substituted aryl, or        —CH₂—O-optionally substituted heteroaryl;    -   R^(c) is independently H, optionally substituted (C₁-C₆)alkyl,        optionally substituted (C₃-C₆)cycloalkyl, optionally substituted        saturated or partially saturated heterocyclyl, optionally        substituted aryl or optionally substituted heteroaryl;    -   R^(d) is H, optionally substituted heterocyclyl,        —(CH₂)-optionally substituted (C₃-C₆)cycloalkyl,        —(CH₂)-optionally substituted heteroaryl or optionally        substituted (C₁-C₃)alkyl;    -   R^(f) is optionally substituted (C₁-C₃)alkyl, optionally        substituted (C₂-C₄)alkenyl or optionally substituted        (C₂-C₄)alkynyl; and    -   n is independently 0 or 1.

In a second embodiment the invention provides a compound according tothe first embodiment, wherein Y is CR¹ and R¹ of Y is H, optionallysubstituted ethenyl, optionally substituted ethyl, optionallysubstituted methyl, optionally substituted 2,3-dihydrobenzofuranyl,optionally substituted 1,4-dioxanyl, optionally substituted3,4-dihydro-2H-benzo[b][1,4]oxazinyl, optionally substituted6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, optionally substitutedchromanyl, optionally substituted cyclohexenyl, optionally substitutedcyclopropyl, optionally substituted tetrahydrofuranyl, optionallysubstituted isochromanyl, optionally substituted1,2,3,4-tetrahydro-isoquinolinyl, optionally substituted isoxazolyl,optionally substituted morpholinyl, optionally substituted oxetanyl,optionally substituted phenyl, optionally substituted piperidinyl,optionally substituted piperazinyl, optionally substituted3,6-dihydro-2H-pyranyl, optionally substituted pyrano[4,3-b]pyridinyl,optionally substituted pyrazolyl, optionally substituted pyridinyl,optionally substituted 3H-pyridin-1-one, optionally substituted1,2,3,6-tetrahydropyridinyl, optionally substituted pyrimidinyl,optionally substituted pyrrolidinyl, optionally substituted2,5-dihydropyrrolyl, optionally substituted tetrahydropyranyl oroptionally substituted tetrahydro-2H-thiopyranyl.

In a third embodiment the invention provides a compound according to anyof the foregoing embodiments wherein R¹ is H or R¹ is optionallysubstituted by one or more substituents independently selected from thegroup consisting of CN, OH, ═O, halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,—CH₂CH₂OH, —CH₂C(CH₃)₂OH,—CH₂CH(OH)CH₂OH, —CH═CH₂, —CH₂NH₂,—CH₂N(H)C(O)R^(e), —C(O)(C₁-C₄)alkyl, —C(O)(C₁-C₄)alkoxy, —C(O)NH₂,—C(O)N(CH₃)₂,—C(O)-optionally substituted heterocyclyl, —N(H)C(O)CH₃,N(CH₃)₂, —S(O)₂(C₁-C₄)alkyl, —S(O)₂-pyrrolidinyl, (C₁-C₄)alkoxy,—CH₂-morpholinyl, —CH₂CH₂-morpholinyl, morpholinyl, tetrahydropyranyl;

-   -   wherein R^(e) is (C₁-C₃)alkyl, —CH₂Cl, —C≡CH, —C≡CCH₃, —CH═CH₂,        —CH═CHCH₃, —C(═CH₂)CH₃, —CH₂CN, —CH₂CH₂N(CH₃)₂,        —CH₂CH₂-piperidinyl, —CH₂O-optionally substituted phenyl.

In a fourth embodiment the invention provides a compound according toany of the foregoing embodiments wherein R³ is —N(H)C(O)CH═CH₂,optionally substituted isoxazolyl, optionally substituted phenyl,optionally substituted pyrazolyl, optionally substituted pyridinyl,optionally substituted pyrimidinyl, optionally substituted thiazolyl, oroptionally substituted thienyl.

In a fifth embodiment the invention provides a compound according to anyof the foregoing embodiments according to claim 4, wherein R³ isoptionally substituted by one or more substituents independentlyselected from —NH₂, —NHCH₃, (C₁-C₄)alkyl and —C(O)(C₂-C₄)alkenyl.

In a sixth embodiment the invention provides a compound according to anyof the foregoing embodiments wherein X is NR² and R² is H.

In a seventh embodiment the invention provides a compound according toany of the foregoing embodiments wherein Y is CR¹ and R¹ of Y is H,optionally substituted phenyl, optionally substituted piperazinyl,optionally substituted pyrazolyl, or optionally substituted1,2,3,6-tetrahydropyridinyl.

In an eighth embodiment the invention provides a compound according toany of the foregoing embodiments wherein Y is CR¹ and R¹ of Y isoptionally substituted by one or more substituents independentlyselected from halogen, (C₁-C₄)alkyl, —C(O)(C₁-C₄)alkyl, and—S(O)₂(C₁—C₄)alkyl.

In a ninth embodiment the invention provides a compound according to anyof the foregoing embodiments wherein

Z is N or Z is CR¹ and R¹ of Z is H; and

A is CR⁴ and R⁴ is H or azetidinyl substituted with —C(O)CH═CH₂.

In a tenth embodiment the invention provides a compound according to anyof the foregoing embodiments wherein the compound is

-   4-(3-amino-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   2-(4-fluorophenyl)-4-(pyridin-3-yl)-1H-indole-7-carboxamide;-   4-(pyridin-3-yl)-2-p-tolyl-1H-indole-7-carboxamide;-   2-(4-fluorophenyl)-4-(pyridin-4-yl)-1H-indole-7-carboxamide;-   2-(4-fluorophenyl)-4-(1H-pyrazol-5-yl)-1H-indole-7-carboxamide;-   4-(3,5-dimethylisoxazol-4-yl)-2-p-tolyl-1H-indole-7-carboxamide;-   2-(1-acetylpiperidin-4-yl)-4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide;-   4-(pyridin-4-yl)-2-p-tolyl-1H-indole-7-carboxamide;-   4-(thiophen-2-yl)-2-p-tolyl-1H-indole-7-carboxamide;-   4-(2-aminophenyl)-1H-indole-7-carboxamide;-   4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide;-   4-(5-aminopyridin-3-yl)-1H-indole-7-carboxamide;-   4-(2-aminopyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-aminoethylamino)-2-(4-fluorophenyl)-1H-indole-7-carboxamide;-   4-(2-aminoethylamino)-2-p-tolyl-1H-indole-7-carboxamide;-   4-(pyrimidin-5-yl)-2-p-tolyl-1H-indole-7-carboxamide;-   4-(1H-pyrazol-4-yl)-2-p-tolyl-1H-indole-7-carboxamide;-   4-(1H-pyrazol-5-yl)-2-p-tolyl-1H-indole-7-carboxamide;-   2-(4-fluorophenyl)-4-(pyrimidin-5-yl)-1H-indole-7-carboxamide;-   4-(thiazol-2-yl)-2-p-tolyl-1H-indole-7-carboxamide;-   4-(pyridin-2-yl)-2-p-tolyl-1H-indole-7-carboxamide;-   4-(thiophen-3-yl)-2-p-tolyl-1H-indole-7-carboxamide;-   4-(1-methyl-1H-pyrazol-4-yl)-2-p-tolyl-1H-indole-7-carboxamide;-   4-(1H-pyrazol-3-yl)-2-p-tolyl-1H-indole-7-carboxamide;-   4-(2-aminophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-phenyl-1H-indole-7-carboxamide;-   4-(3-amino-2-methylphenyl)-2-(4,4-difluorocyclohex-1-enyl)1H-indole-7-carboxamide;-   4-(3-amino-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;-   4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide;-   4-(1-acryloylpiperidin    3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   4-(2-aminoethylamino)-2-p-tolyl-1H-indole-7-carboxamide;-   4-((1R,2R)-2-aminocyclohexylamino)-2-(4-fluorophenyl)-1H-indole-7-carboxamide*;-   4-(1-methyl-1H-pyrazol-5-ylamino)-2-p-tolyl-1H-indole-7-carboxamide;-   4-iodo-2-(pyridin-3-yl)-1H-indole-7-carboxamide;-   4-(3-amino-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3,5-dimethylisoxazol-4-yl)-2-(4-fluorophenyl)-1H-indole-7-carboxamide;-   4-(2-aminophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;    or-   2-(1-Acetylpiperidin-4-yl)-4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide.

In an eleventh embodiment the invention provides a compound according toany of the first through third embodiments wherein R³ is —R³⁰¹-L-R³⁰²,and R³⁰¹ is a bond, N(H), N(CH₃), CH₂, C(H)(optionally substituted(C₁-C₃)alkyl), O, or OCH₂.

In an twelfth embodiment the invention provides a compound according tothe any of the first through third or eleventh embodiments wherein

-   -   L is optionally substituted azetidinyl, optionally substituted        cyclopentyl, optionally substituted        3,6-diazabicyclo[3.2.0]heptanyl, optionally substituted        1,4-dioxanyl, optionally substituted morpholinyl, optionally        substituted [1,4]oxepanyl, optionally substituted phenyl,        optionally substituted piperidinyl, or optionally substituted        pyrrolidinyl; or    -   L is L¹-L² wherein        -   L¹ is optionally substituted cyclohexyl, optionally            substituted cyclopentyl optionally substituted phenyl,            optionally substituted piperidinyl, optionally substituted            pyridinyl;        -   L² is N(H), N(CH₃), N(CH₂CH₂OH), N(CH₂CH(CH₃)₂),            N(oxetanyl), N(CH₂-cyclopentyl), N(CH₂-thiazolyl), O,            S(O)₂N(H), or CH₂N(H).

In an thirteenth embodiment the invention provides a compound accordingto any of the first through third and eleventh and twelfth embodimentswherein L or L¹ is optionally substituted with one or more substituentsindependently selected from halogen, CN, OH, (C₁-C₄)alkoxy,(C₁-C₄)alkyl, —CH₂OH, —N(H)CH₂-heteroaryl, benzyloxy, and—OCH₂-heteroaryl.

In an fourteenth embodiment the invention provides a compound accordingto any of the first through third and eleventh through thirteenthembodiments wherein R³⁰² is —C(O)CH₃, —C(O)C(O)CH₃, —C(O)CF₂(Cl),—CH(CH₃)₂, —CH₂Cl, —CH₂CN, —C(O)CH₂CN, —C(O)CH₂CH₃, —C(O)CH₂F,—C(O)CH(CH₃)₂, —C(O)—CH₂CH(CH₃)₂, —C(O)CH(CH₃)(C), —C(O)CH₂CH(CH₃)CH₃,—C(O)CH(Cl)CH₂CH₃, —CH₂CH₂OH, —C(O)CH₂CH₂N(CH₃)₂, —C(O)CH═CH₂,—C(O)C≡CH, —C(O)CH═CHCl, —C(O)CH═CHCH₃, —C(O)C(═CH₂)CH₃,—C(O)C(CH₂CH₃)═CH₂, —C(O)CH═CHCH(CH₃)₂, —C(O)CH═CHC(O)OH,—C(O)CH═CHC(O)N(H)CH₂CH₃, —C(O)CH═CHCH₂N(CH₃)₂, —C(O)CH═CHC(O)OCH₃,—C(O)CH═CHC(O)OCH₂CH₃, —C(O)CH═CHC(O)N(H)CH₃, —C(O)CH═CHC(O)CH₂CH₂OCH₃,—C(O)CH═CHC(O)N(CH₃)₂, —C(O)CH═CHC(O)N(H)CH₂CH₃,—C(O)CH═CHC(O)N(H)CH₂CH₂OCH₃, —C(O)CH═CHCH₂N(H)CH₂CH₂OCH₃,—C(O)C(CN)═C(OH)(CH₃), —C(O)CH═CH-optionally substitutedpyrazolyl-C(O)CH═CHCH₂N(H)-optionally substituted cyclopropyl,—C(O)CH═CHCH₂N(H)CH₂-optionally substituted tetrahydrofuranyl,—C(O)CH═CHC(O)NH₂,—C(O)CH═CHC(O)N(H)— optionally substitutedcyclopropyl, —C(O)C(CH₃)═CHCH₃, —C(O)C(CH₃)═CHCH₂CH₃,—C(O)C(═CH₂)CH₂N(CH₃)₂, —C(O)C(═CH₂)CH₂NH₂, —C(O)C(═CH₂)CH₂N(H)(CH₃),—C(O)C(═CH₂)CH₃, —C(O)C(═CH₂)CH₂— optionally substituted morpholinyl,—C(O)C(═CH₂)-optionally substituted phenyl, —CH₂-optionally substitutedbenzo[d]isothiazolyl, —C(O)—CH₂—O-optionally substituted phenyl,—CH₂-optionally substituted thiazolyl, —CH₂CH₂-optionally substitutedmorpholinyl, —C(O)CH₂O-optionally substituted phenyl,—C(O)CH₂CH₂-optionally substituted piperazinyl, —C(O)CH₂CH₂— optionallysubstituted piperidinyl, —C(O)CH₂O-optionally substituted pyridinyl,—C(O)CH₂CH₂ optionally substituted pyrrolidinyl,—C(O)CH═CH optionallysubstituted cyclopropyl,—C(O)CH═CHCH₂— optionally substitutedmorpholinyl, —C(O)CH═CHCH₂— optionally substitutedpiperidinyl,—C(O)CH═CH-optionally substitutedpyrazolyl,—C(O)CH═CH-optionally substituted pyridinyl,—C(O)CH═CH-optionally substituted thiazolyl, —C(O)-optionallysubstituted cyclohexenyl, —C(═O)-optionally substituted cyclohexyl,—C(O)-optionally substituted cyclopentenyl, —C(O)-cyclopentyl,optionally substituted imidazo[1,2-a]pyrazinyl, optionally substitutedtetrahydroimidazo[1,2-a]pyrazinyl, optionally substituteddihydr-isoindolyl, optionally substituted1,2,3,4-tetrahydro-isoquinolinyl, optionally substituted isoquinolinyl,—C(O)-optionally substituted isoxazolyl, —C(O)-optionally substitutedoxazolyl, optionally substituted oxetanyl,—C(═O)— optionally substitutedphenyl, optionally substituted piperidinyl, —C(O)-optionally substitutedpiperidinyl, optionally substituted pyrazolyl, —C(O)CH₂O-optionallysubstituted pyridazinyl, —C(O)-optionally substituted pyridinyl,optionally substituted pyrimidinyl, optionally substituted quinazolinyl,optionally substituted dihydroquinolinyl, optionally substituted—C(O)-tetrahydrobenzo[b]thiophenyl, —C(O)-optionally substitutedtetrahydropyranyl, —C(O)-optionally substituted tetrahydropyridinyl,—C(O)-thiazolyl, —C(O)N(H)-thiazolyl, —C(O)NHCH₂CN, or —S(O)₂CH═CH₂.

In a fifteenth embodiment the invention provides a compound according toany of the first through third or thirteenth through fourteenthembodiments wherein X is NR² and R² is H.

In a sixteenth embodiment the invention provides a compound according toany of the first through third or thirteenth through fifteenthembodiments wherein Y is CR¹ and R¹ of Y is optionally substituted withone or more substituents independently selected from halogen, CN, ═O,(C₁-C₄)alkyl, (C₂-C₄)alkenyl, —CH₂NH₂, —CH₂CH₂OH, —CH₂CH(OH)CH₂CH₃,—CH₂CH(OH)CH₂OH, —CH₂CH₂OCH₂CH₃, —CH₂C(OH)(CH₃)₂,—CH₂NHC(O)(C₁-C₄)alkyl, —CH₂NHC(O)CH₂Cl, —CH₂NHC(O)CH₂CN,—CH₂NHC(O)CH₂CH₂N(CH₃)₂, —CH₂NHC(O)C(═CH₂)CH₃, —CH₂NHC(O)(C₂-C₄)alkynyl,—CH₂NHC(O)CH₂CH₂-piperidinyl, —(C₁-C₄)alkyl-morpholinyl,—CH₂NHC(O)CH₂O-phenyl wherein the phenyl is optionally substituted withhalogen, (C₁-C₄)alkoxy, —C(O)(C₁-C₄)alkyl, —C(O)(C₁-C₄)alkoxy,—C(O)N(H)₂, —C(O)N(CH₃)₂, —C(O)-morpholinyl, —C(O)-pyrrolidinyl,—N(CH₃)₂, —NHC(O)(C₁-C₄)alkyl, —NHC(O)(C₂-C₄)alkenyl, —NHC(O)CH₂CN,—S(O)₂(C₁-C₄)alkyl, —S(O)₂-pyrrolidinyl, morpholinyl, tetrahydropyranyl,or 4-methylpiperazinecarbonyl.

In a seventeenth embodiment the invention provides a compound accordingto any of the first through third or thirteenth through sixteenthembodiments wherein Z is CR¹ and R¹ of Z is H, (C₁-C₄)alkyl,—NHC(O)CH₂Cl, —NHC(O)CH₂CN, —NHC(O)(C₂-C₄)alkenyl,—NHC(O)(C₂-C₄)alkynyl, —NHC(O)C(═CH₂)CH₃, —NHC(O)CH₂-phenyl wherein thephenyl is optionally substituted with halogen, or pyrazolyl substitutedwith CH₃.

In a eighteenth embodiment the invention provides a compound accordingto any of the first through third or thirteenth through seventeenthembodiments wherein R³⁰² is optionally substituted with one or moresubstituents independently selected from halogen, CF₃, OCF₃, ═O, CHF₂,CN, C(O)OH, OH, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₃-C₆)cycloalkyl,—(C₁-C₄)alkylCN, —(C₁-C₄)alkylC(O)NH₂, —C(O)NH₂, —C(O)N(H)(C₁-C₄)alkyl,—C(O)N(C₁-C₄)alkyl)₂, —C(O)N(H)cyclopropyl, —C(O)(C₁-C₄)alkoxy, NH₂,N(H)CH₃, N(CH₃)₂, or optionally substituted benzyl.

In a nineteenth embodiment the invention provides a compound accordingto any of the first through third or thirteenth through eighteenthembodiments wherein

X is NR² wherein R² is H;

Y is CR wherein R¹ is H, CH₃, substituted pyrazolyl,6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl or tetrahydrofuranyl;

Z is CR wherein R is H;

E is CR wherein R is H;

R³ is —R³⁰¹-L-R³⁰² wherein

-   -   R³⁰¹ is a bond, —O—, —N(H)—, —N(CH₃)— or —C(H)(CH₃)—;    -   L is azetidinyl, 3,6-diazabicyclo[3.2.0]heptanyl, morpholinyl,        [1,4]oxepanyl, piperidinyl, or pyrrolidinyl;        -   wherein the azetidinyl is optionally substituted with CH₃;            and        -   wherein the piperidinyl is optionally substituted with            —CH₂OH; and    -   R³⁰² is —C(O)CH═CH₂ or —C(O)C≡CH.

In a twentieth embodiment the invention provides a compound according toany of the first through third or thirteenth through nineteenthembodiments wherein the compound is:

-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-1H-indole-7-carboxamide;-   4-(5-acetylthiophen-2-yl)-2-p-tolyl-1H-indole-7-carboxamide;-   4-(1-(4-methoxybenzyl)-1H-pyrazol-5-ylamino)-2-p-tolyl-1H-indole-7-carboxamide;-   4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;-   4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)phenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;-   4-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;-   4-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-2-(4-fluorophenyl)-1H-indole-7-carboxamide;-   2-(4-fluorophenyl)-4-(2-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)phenyl)-1H-indole-7-carboxamide;-   N-(3-(7-carbamoyl-2-(pyridin-3-yl)-1H-indol-4-yl)-4-methylphenyl)thiazole-2-carboxamide    2,2,2-trifluoroacetate;-   N-(3-(7-carbamoyl-2-(pyridin-3-yl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   (R)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide*;-   (R)-2-(4-fluorophenyl)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide*;-   (R)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide*;-   (R)-2-(1-methyl-1H-pyrazol-4-yl)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide*;-   (R)-4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-2-(4-fluorophenyl)-1H-indole-7-carboxamide*;-   2-(1-methyl-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;-   2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;-   (R)-4-(3-(4-tert-butylbenzamido)piperidin-1-yl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide*;-   (R)-4-(3-(4-tert-butylbenzamido)piperidin-1-yl)-1H-indole-7-carboxamide*;-   (R)—N-(1-(7-carbamoyl-1H-indol-4-yl)piperidin-3-yl)-2-methyloxazole-4-carboxamide*;-   (R)-4-(3-(3-thiazol-2-ylureido)piperidin-1-yl)-1H-indole-7-carboxamide*;-   4-(3-(4-tert-butylbenzamido)-2-methylphenyl)-1H-indole-7-carboxamide;-   4-(3-(7-cyclopropyl-5-fluoro-4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide;-   (R)-4-(3-(4-tert-butylbenzamido)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide*;-   (R)-4-(3-(4-methoxybenzamido)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide*;-   (R)-5-tert-butyl-N-(1-(7-carbamoyl-1H-indol-4-yl)piperidin-3-yl)isoxazole-3-carboxamide*;-   (R)-2-(1-methyl-1H-pyrazol-4-yl)-4-(3-(4-(trifluoromethyl)benzamido)piperidin-1-yl)-1H-indole-7-carboxamide*;-   (R)-4-(3-(4-methoxybenzamido)piperidin-1-yl)-1H-indole-7-carboxamide*;-   (R)-4-(3-(4-(trifluoromethyl)benzamido)piperidin-1-yl)-1H-indole-7-carboxamide*;-   (R)-4-(3-(4-(difluoromethyl)benzamido)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide*;-   4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;-   2-(4-fluorophenyl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;-   (R)-4-(3-(4-(1-amino-2-methyl-1-oxopropan-2-yl)benzamido)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide*;-   (R)-2-(1-methyl-1H-pyrazol-4-yl)-4-(3-(4-(trifluoromethoxy)benzamido)piperidin-1-yl)-1H-indole-7-carboxamide*;-   2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;-   (R)-4-(3-(6-fluoro-1-oxoisoindolin-2-yl)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide*;-   2-(3,6-dihydro-2H-pyran-4-yl)-4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide;-   2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide;-   N-(3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(hydroxymethyl)phenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   2-(1-methyl-1H-pyrazol-4-yl)-4-(2-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)phenyl)-1H-indole-7-carboxamide;-   (R)-4-(3-(4-cyclopropylbenzamido)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide*;-   2-(2,5-dihydro-1H-pyrrol-3-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   2-(1-((R)-2,3-dihydroxypropyl)-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide*;-   N-(3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)-2-(hydroxymethyl)phenyl)thiazole-2-carboxamide;-   2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(4-tert-butylbenzamido)-2-methylphenyl)-1H-indole-7-carboxamide;-   N-(3-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)phenyl)-1H-indole-7-carboxamide;-   2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(4-cyclopropylbenzamido)-2-methylphenyl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   2-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;-   2-(1-acetyl-2,5-dihydro-1H-pyrrol-3-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;-   ethyl    3-(7-carbamoyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate;-   2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   N-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   2-(1-((S)-2,3-dihydroxypropyl)-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;-   N-(3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)-2-methylphenyl)-N-methylthiazole-2-carboxamide;-   N-(3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)-2-methylphenyl)-N-(oxetan-3-yl)thiazole-2-carboxamide;-   2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(4-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-(pyrimidin-5-yl)-1H-indole-7-carboxamide;-   4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-2-(pyrimidin-5-yl)-1H-indole-7-carboxamide;-   4-(3-(4-(difluoromethyl)benzamido)-2-methylphenyl)-2-(pyrimidin-5-yl)-1H-indole-7-carboxamide;-   4-(3-(4-cyclopropylbenzamido)-2-methylphenyl)-2-(pyrimidin-5-yl)-1H-indole-7-carboxamide;-   4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   (R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide*;-   (R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(8-oxoimidazo[1,2-a]pyrazin-7(8H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide*;-   4-(2-methyl-3-(oxetan-3-ylamino)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(4-(difluoromethyl)benzamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(4-hydroxy-4-(trifluoromethyl)cyclohexanecarboxamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   (R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide*;-   2-(1-acetylpiperidin-4-yl)-4-(3-(4-cyclopropylbenzamido)-2-methylphenyl)-1H-indole-7-carboxamide;-   (R)—N-(1-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)piperidin-3-yl)-2-methyloxazole-4-carboxamide*;-   (R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-oxo-1,3′-bipiperidin-1′-yl)-1H-indole-7-carboxamide*;-   2-(1-methyl-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-benzo[d]imidazole-7-carboxamide;-   4-(3-(4-(difluoromethyl)-N-(oxetan-3-yl)benzamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(oxetan-3-ylamino)phenyl)-1H-indole-7-carboxamide;-   4-(3-(4-(difluoromethyl)benzamido)-2-methylphenyl)-1H-indole-7-carboxamide;-   4-(3-(2-hydroxyethylamino)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   (R)—N-(1-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)piperidin-3-yl)thiazole-2-carboxamide*;-   4-(3-(cyclohexanecarboxamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(4-(difluoromethyl)-N-(2-hydroxyethyl)benzamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   N-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl)isothiazole-4-carboxamide;-   4-(2-methyl-3-(tetrahydro-2H-pyran-4-carboxamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(1-methylpiperidine-3-carboxamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(1-methylpiperidine-4-carboxamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(cyclopentanecarboxamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   N-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl)-2-methylthiazole-4-carboxamide;-   4-(3-(3-methoxycyclohexanecarboxamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(3-methylbutanamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-isobutyramido-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(nicotinamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   N-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl)-5-methylthiazole-2-carboxamide;-   N-(3-(7-carbamoyl-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-((3R,4R)-1-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-4-hydroxypiperidin-3-yl)thiazole-2-carboxamide;-   (R)-4-(3-acrylamidopiperidin-1-yl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide*;-   4-(2-methyl-3-(thiazol-2-ylmethylamino)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(N-(thiazol-2-ylmethyl)acrylamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   (Z)-4-(2-methyl-3-(2-methylbut-2-enamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   (E)-4-(3-(4-(dimethylamino)but-2-enamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(3-(piperidin-1-yl)propanamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(2-cyanoacetamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-propionamidophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-methacrylamido-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamidel;-   4-(3-(2-chloro-2,2-difluoroacetamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(2-chloropropanamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   (E)-4-(3-but-2-enamido-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   N1-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl);-   4-(3-(2-(4-fluorophenoxy)acetamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(3-(pyrrolidin-1-yl)propanamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(2-(4-cyanophenoxy)acetamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(2-(pyridin-3-yloxy)acetamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(cyclopent-1-enecarboxamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   (E)-4-(2-methyl-3-(2-methylpent-2-enamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   (Z)-4-(3-(3-chloroacrylamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   (E)-methyl    4-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenylamino)-4-oxobut-2-enoate;-   4-(3-(cyclohex-1-enecarboxamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   (E)-ethyl    4-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenylamino)-4-oxobut-2-enoate;-   4-(2-methyl-3-(2-phenoxyacetamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(2-fluoroacetamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(4,4-difluorocyclohex-1-enyl)-1H-indole-7-carboxamide;-   4-(2-(acrylamidomethyl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(3-(dimethylamino)propanamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-acrylamidophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(acrylamidomethyl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(acrylamidomethyl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(2-cyanopyrimidin-4-ylamino)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamidophenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(2-methoxypyridin-3-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(2-(pyridin-2-yloxy)acetamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   N1-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl)fumaramide;-   4-(3-(2-chlorobutanamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(3-(4-methylpiperazin-1-yl)propanamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(2-(pyridazin-3-yloxy)acetamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(thiazol-2-ylmethoxy)phenyl)-1H-indole-7-carboxamide;-   methyl    3-(4-(3-acrylamido-2-methylphenyl)-7-carbamoyl-1H-indol-2-yl)benzoate;-   4-(3-acrylamido-2-methylphenyl)-2-(3-methoxyphenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(4-methoxyphenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(6-methylpyridin-3-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(3-carbamoylphenyl)-1H-indole-7-carboxamide;-   N-(3-(7-carbamoyl-3-methyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(1-isopropyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(1-ethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(1-isobutyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   (E)-N-(3-(3-but-2-enamido-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(7-carbamoyl-3-methacrylamido-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(3-but-2-ynamido-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(7-carbamoyl-3-(2-(4-fluorophenoxy)acetamido)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(2-fluoropyridin-3-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(1-ethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   2-(3-acetamidophenyl)-4-(3-acrylamido-2-methylphenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(2-methoxypyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(3-cyanophenyl)-1H-indole-7-carboxamide;-   methyl    4-(4-(3-acrylamido-2-methylphenyl)-7-carbamoyl-1H-indol-2-yl)benzoate;-   4-(3-acrylamido-2-methylphenyl)-2-(2,3-dihydrobenzofuran-5-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(3-fluorophenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(3-(dimethylamino)phenyl)-1H-indole-7-carboxamide;-   4-(2-(2-chloroacetamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-acetamidophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(2-methyl-5-(pyrrolidin-1-ylsulfonyl)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(2-fluorophenyl)-1H-indole-7-carboxamide;-   N-(3-(3-acrylamido-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(7-carbamoyl-3-(2-chloroacetamido)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(1-methyl-1H-pyrazol-5-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(pyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(6-morpholinopyridin-3-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(3-(4-methylpiperazine-1-carbonyl)phenyl)-1H-indole-7-carboxamide;-   N-(3-(2-(2-(acrylamidomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(2-(2-(acetamidomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(7-carbamoyl-2-(2-(propionamidomethyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(2-(2-(butyramidomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   (E)-N-(3-(2-(2-(but-2-enamidomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(7-carbamoyl-2-(2-(methacrylamidomethyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(7-carbamoyl-2-(2-(propiolamidomethyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(2-(2-(but-2-ynamidomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(7-carbamoyl-2-(2-((2-cyanoacetamido)methyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(7-carbamoyl-2-(2-((3-(dimethylamino)propanamido)methyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(7-carbamoyl-2-(2-((3-(piperidin-1-yl)propanamido)methyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(7-carbamoyl-2-(2-((2-phenoxyacetamido)methyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(7-carbamoyl-2-(2-((2-(4-fluorophenoxy)acetamido)methyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(7-carbamoyl-2-(2-((2-chloroacetamido)methyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   N-(3-(2-(2-(aminomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(4-fluorophenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-phenyl-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(2-(methylsulfonyl)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(4-(dimethylcarbamoyl)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(pyrimidin-5-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(4-(morpholine-4-carbonyl)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(4-(pyrrolidine-1-carbonyl)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(4-(methylsulfonyl)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(6-methoxypyridin-3-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(4-cyanophenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(2-methoxyphenyl)-1H-indole-7-carboxamide;-   N-(3-(7-carbamoyl-3-(2-cyanoacetamido)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;-   4-(2-acrylamidophenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(4-(morpholinomethyl)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(4-carbamoylphenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-5-(thiazol-2-ylmethylamino)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide;-   4-(3-(methylamino)phenyl)-1H-indole-7-carboxamide;-   4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(2-methylenebutanamido)phenyl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(3-(pyrrolidin-1-yl)propanamido)phenyl)-1H-indole-7-carboxamide;-   4-(3-methacrylamido-2-methylphenyl)-1H-indole-7-carboxamide;-   (E)-4-(3-(3-cyclopropylacrylamido)-2-methylphenyl)-1H-indole-7-carboxamide;-   (E)-4-(2-methyl-3-(3-(pyridin-2-yl)acrylamido)phenyl)-1H-indole-7-carboxamide;-   (E)-4-(2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)acrylamido)phenyl)-1H-indole-7-carboxamide;-   (E)-ethyl    4-(3-(7-carbamoyl-1H-indol-4-yl)-2-methylphenylamino)-4-oxobut-2-enoate;-   (E)-4-(3-(4-(dimethylamino)but-2-enamido)-2-methylphenyl)-1H-indole-7-carboxamide;-   (E)-4-(2-methyl-3-(3-(pyridin-3-yl)acrylamido)phenyl)-1H-indole-7-carboxamide;-   (E)-4-(2-methyl-3-(4-methylpent-2-enamido)phenyl)-1H-indole-7-carboxamide;-   N1-(3-(7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)-N4-ethylmaleamide;-   4-(3-acetamido-2-methylphenyl)-1H-indole-7-carboxamide;-   (E)-4-(3-but-2-enamido-2-methylphenyl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(3-morpholinopropanamido)phenyl)-1H-indole-7-carboxamide;-   (E)-4-(2-methyl-3-(3-(thiazol-2-yl)acrylamido)phenyl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(2-phenylacrylamido)phenyl)-1H-indole-7-carboxamide;-   (E)-4-(2-methyl-3-(4-(piperidin-1-yl)but-2-enamido)phenyl)-1H-indole-7-carboxamide;-   (E)-4-(2-methyl-3-(4-((tetrahydrofuran-2-yl)methylamino)but-2-enamido)phenyl)-1H-indole-7-carboxamide;-   (E)-4-(3-(4-(2-methoxyethylamino)but-2-enamido)-2-methylphenyl)-1H-indole-7-carboxamide;-   (E)-4-(3-(4-(cyclopropylamino)but-2-enamido)-2-methylphenyl)-1H-indole-7-carboxamide;-   (E)-4-(2-methyl-3-(4-morpholinobut-2-enamido)phenyl)-1H-indole-7-carboxamide;-   (E)-4-(2-methyl-3-(4-(4-methylpiperazin-1-yl)but-2-enamido)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-4-(benzyloxy)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-5-(benzyloxy)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-4-(thiazol-2-ylmethoxy)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-5-(thiazol-2-ylmethoxy)phenyl)-1H-indole-7-carboxamide;-   4-(2-acrylamido-4-(thiazol-2-ylmethoxy)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;-   4-(2-acrylamido-4-(benzyloxy)phenyl)-1H-indole-7-carboxamide;-   4-(5-acrylamidopyridin-3-yl)-1H-indole-7-carboxamide;-   4-(2-acrylamidopyridin-4-yl)-1H-indole-7-carboxamide;-   N1-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-N4-(2-methoxyethyl)maleamide;-   N1-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-N4-ethylmaleamide;-   4-(3-(1-methyl-1,2,5,6-tetrahydropyridine-3-carboxamido)phenyl)-1H-indole-7-carboxamide;-   4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide;-   4-(3-(2-oxopropanamido)phenyl)-1H-indole-7-carboxamide;-   (E)-methyl    4-(3-(7-carbamoyl-1H-indol-4-yl)phenylamino)-4-oxobut-2-enoate;-   4-(3-(cyanomethylcarbamoyl)phenyl)-1H-indole-7-carboxamide;-   N-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-5-methylisoxazole-4-carboxamide;-   N1-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-N4-methylfumaramide;-   N1-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-N4,N4-dimethylfumaramide;-   N1-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-N4-ethylfumaramide;-   N1-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-N4-cyclopropylfumaramide;-   (E)-4-(3-(7-carbamoyl-1H-indol-4-yl)phenylamino)-4-oxobut-2-enoic    acid;-   4-(3-(N-isobutylacrylamido)phenyl)-1H-indole-7-carboxamide;-   1-Acryloyl-1,2,3,6-tetrahydro-pyrrolo[2,3-e]indole-5-carboxylic acid    amide;-   4-acrylamido-1H-indole-7-carboxamide;-   4-(3-(N-(cyanomethyl)sulfamoyl)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamidophenyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;-   4-(3-((2-oxopropanamido)methyl)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamidophenyl)-1H-indazole-7-carboxamide;-   4-(3-acrylamido-2-methoxyphenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-fluorophenyl)-1H-indole-7-carboxamide;-   4-(5-acrylamido-2-fluorophenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-4-fluorophenyl)-1H-indole-7-carboxamide;-   4-(5-acrylamido-2-chlorophenyl)-1H-indole-7-carboxamide;-   4-(5-acrylamido-2,4-difluorophenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-4-cyanophenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2,6-difluorophenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-5-methylphenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-4-methylphenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-4-methoxyphenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-5-methoxyphenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-4-chlorophenyl)-1H-indole-7-carboxamide;-   4-(5-acrylamido-2,3-difluorophenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-5-cyanophenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-cyanophenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamidophenyl)-2-vinyl-1H-indole-7-carboxamide;-   4-(3-acrylamidophenyl)-2-ethyl-1H-indole-7-carboxamide;-   4-(3-(2-(morpholinomethyl)acrylamido)phenyl)-1H-indole-7-carboxamide;-   4-(3-(2-((dimethylamino)methyl)acrylamido)phenyl)-1H-indole-7-carboxamide;-   (E)-4-(3-(4-(dimethylamino)but-2-enamido)-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;-   4-((1R,3S)-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;-   4-(cis-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;-   4-((1S,3S)-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;-   4-(trans-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;-   4-(cis-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;-   4-(3-(2-(aminomethyl)acrylamido)phenyl)-1H-indole-7-carboxamide;-   4-((1R,3S)-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;-   4-(3-(2-((methylamino)methyl)acrylamido)phenyl)-1H-indole-7-carboxamide;-   4-(3-acrylamidophenyl)-2-methyl-1H-indole-7-carboxamide;-   4-((1S,3S)-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;-   4-(3-acrylamidophenyl)-2-(2-ethoxyethyl)-1H-indole-7-carboxamide;-   4-(3-acrylamidophenyl)-2-(2-hydroxyethyl)-1H-indole-7-carboxamide;-   4-(1-acryloylpiperidin    3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   4-(3-acrylamido-2-methylphenyl)-2-(1-isopropyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   4-(3-(4-cyclopropylbenzamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(2-methyl-3-(1-methylpiperidine-4-carboxamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;-   4-(3-(N-(cyclopentylmethyl)acrylamido)phenyl)-1H-indole-7-carboxamide;-   ethyl    4-(7-carbamoyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol-2-yl)5,6-dihydropyridine-1(2H)-carboxylate;-   (R)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1H-indole-7-carbonitrile;-   4-(2,6-dichlorobenzyl)-2-(p-tolyl)-1H-indole-7-carboxamide;-   (E)-4-(3-(2-cyano-3-hydroxybut-2-enamido)phenyl)-1H-indole-7-carboxamide;-   4-(cis-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;-   4-(trans-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;-   4-(trans-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)oxy)-1H-indole-7-carboxamide;-   (S)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide;-   (R)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide*;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;-   (R)-4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide*;-   (S)-4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide*;-   (S)-4-(1-acryloylpiperidin-3-yl)-2-methyl-1H-indole-7-carboxamide;-   (R)-4-(1-acryloylpiperidin-3-yl)-2-methyl-1H-indole-7-carboxamide;-   (R)-4-(4-acryloylmorpholin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   (S)-4-(4-acryloylmorpholin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   (R)-4-(1-acryloylpyrrolidin-3-yl)-2-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-1H-indole-7-carboxamide;-   2-methyl-4-(methyl(1-propioloylazetidin-3-yl)amino)-1H-indole-7-carboxamide;-   (S)-4-(1-acryloylpyrrolidin-3-yl)-2-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-1H-indole-7-carboxamide;-   (R)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;-   (S)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;-   (R)-4-(1-acryloylpiperidin-3-yl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;-   (S)-4-(1-acryloylpiperidin-3-yl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;-   (R)-7-(1-acryloylpiperidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridine-4-carboxamide;-   (S)-7-(1-acryloylpiperidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridine-4-carboxamide;-   (S)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-indole-7-carboxamide;-   4-((3S,5R)-1-acryloyl-5-(hydroxymethyl)piperidin-3-yl)-1H-indole-7-carboxamide;-   4-((3S,5S)-1-acryloyl-5-(hydroxymethyl)piperidin-3-yl)-1H-indole-7-carboxamide;-   4-((3R,5S)-1-acryloyl-5-(hydroxymethyl)piperidin-3-yl)-1H-indole-7-carboxamide;-   4-((3R,5R)-1-acryloyl-5-(hydroxymethyl)piperidin-3-yl)-1H-indole-7-carboxamide;-   (R)-4-(1-acryloylpyrrolidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   (S)-4-(1-acryloylpyrrolidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   4-((1R,3R)-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;-   (S)-4-(1-acryloylpiperidin-3-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;-   (R)-4-(1-acryloylpiperidin-3-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;-   (R)-2-methyl-4-(1-propionylpyrrolidin-3-yl)-1H-indole-7-carboxamide;-   (S)-2-methyl-4-(1-propionylpyrrolidin-3-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(isochroman-7-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(4,4-difluorocyclohex-1-en-1-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(4-(methylsulfonyl)cyclohex-1-en-1-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(6-morpholinopyridin-3-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(chroman-7-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(5-(morpholinomethyl)pyridin-2-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1-methyl-1H-pyrazol-5-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1-propylpiperidin-4-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(tetrahydrofuran-3-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(3-hydroxyoxetan-3-yl)-1H-indole-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-methyl-1H-indole-7-carboxamide;-   (R)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-indole-7-carboxamide;-   (S)-4-(1-acryloylpyrrolidin-3-yl)-2-methyl-1H-indole-7-carboxamide*;-   (R)-4-(1-acryloylpyrrolidin-3-yl)-2-methyl-1H-indole-7-carboxamide*;-   4-((1R,5S)-6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-1H-indole-7-carboxamide;-   4-((1S,5R)-6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-1H-indole-7-carboxamide;-   (R)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;-   (S)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;-   4-((1-acryloylazetidin-3-yl)amino)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;-   4-((1-acryloyl-3-methylazetidin-3-yl)(methyl)amino)-1H-indole-7-carboxamide;-   4-((1-cyanoazetidin-3-yl)(methyl)amino)-2-methyl-1H-indole-7-carboxamide;-   4-(2-chloro-6-fluorobenzyl)-2-p-tolyl-1H-indole-7-carboxamide;-   (S)-4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(tetrahydrofuran-3-yl)-1H-indole-7-carboxamide;-   (R)-4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(tetrahydrofuran-3-yl)-1H-indole-7-carboxamide;-   (S)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;-   (R)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;-   (S)-4-(1-acryloylpiperidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;    or-   (R)-4-(1-acryloylpiperidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide.

In a twenty-first embodiment the invention provides a method of treatinga disease comprising administering a therapeutically effective amount ofa compound of claim 1 to a patient in need thereof.

In a twenty-second embodiment the invention provides a compoundaccording to any of foregoing embodiments, wherein the disease isrheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis,Crohn's disease, inflammatory bowel disease, ulcerative colitis,psoriatic arthritis, psoriasis, ankylosing spondylitis, interstitialcystitis, asthma, systemic lupus erythematosus, lupus nephritis, B cellchronic lymphocytic lymphoma, multiple sclerosis, chronic lymphocyticleukemia, small lymphocytic lymphoma, mantle cell lymphoma, B-cellnon-Hodgkin's lymphoma, activated B-cell like diffuse large B-celllymphoma, multiple myeloma, diffuse large B-cell lymphoma, follicularlymphoma, hairy cell leukemia or Lymphoblastic lymphoma.

In a twenty-third embodiment the invention provides kit comprising apackaged product comprising components with which to administer acompound a compound according to any of foregoing embodiments fortreatment of an autoimmune disorder.

In a twenty-fourth embodiment the invention provides a kit according tothe twenty-third embodiment, wherein the packaged product comprises acompound of claim 1 and instructions for use.

In a twenty-fifth embodiment the invention provides a pharmaceuticalcomposition comprising a compound according to any of ht efirst thorughtwentieth embodiments and one or more pharmaceutically acceptableexcipients.

DETAILED DESCRIPTION OF THE INVENTION

Protein kinases are a broad and diverse class, of over 500 enzymes, thatinclude oncogenes, growth factors receptors, signal transductionintermediates, apoptosis related kinases and cyclin dependent kinases.They are responsible for the transfer of a phosphate group to specifictyrosine, serine or threonine amino acid residues, and are broadlyclassified as tyrosine and serine/threonine kinases as a result of theirsubstrate specificity.

The protein kinases represent a large family of proteins that play acentral role in the regulation of a wide variety of cellular processesand maintenance of cellular function. A partial, non-limiting, list ofthese kinases include: non-receptor tyrosine kinases such as the Tecfamily (BTK, ITK, Tec, ETK/BMX & RLK/TXK), Janus kinase family (Jak1,Jak2, Jak3 and Tyk2); the fusion kinases, such as BCR-Abl, focaladhesion kinase (FAK), Fes, Lek and Syk; receptor tyrosine kinases suchas epidermal growth factor receptor (EGFR), the platelet-derived growthfactor receptor kinase (PDGF-R), the receptor kinase for stem cellfactor, c-kit, the hepatocyte growth factor receptor, c-Met, and thefibroblast growth factor receptor, FGFR3; and serine/threonine kinasessuch as b-RAF, mitogen-activated protein kinases (e.g., MKK6) andSAPK2β. Aberrant kinase activity has been observed in many diseasestates including benign and malignant proliferative disorders as well asdiseases resulting from inappropriate activation of the immune andnervous systems. The novel compounds of this invention inhibit theactivity of one or more protein kinases and are, therefore, expected tobe useful in the treatment of kinase-mediated diseases.

Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase with akey role in immunoreceptor signaling (BCR, FcR, FcγR, DAP12, Dectin-1,GPVI, etc.) in a host of hematopoietic cells including B cells,platelets, mast cells, basophils, eosinophils, macrophages andneutrophils as well as osteoclasts involved in bone destruction (forreviews, see Brunner et al., 2005 Histol. Histopathol., 20:945; Mohamedet al., 2009 Immunol. Rev., 228:58). Mutations in BTK are known to leadto X-linked agammaglobulinemia (XLA) in humans and X-linkedimmunodeficiency (Xid) in mice, which are characterized by limitedB-cell production & reduced antibody titers (Lindvall et al., 2005Immunol. Rev., 203:200). The combined action of BTK in multiple celltypes makes it an attractive target for autoimmune disease. BTK isrelated with sequence homology to other Tec family kinases (ITK, Tec,ETK/BMX & RLK/TXK).

In B-lymphocytes, BTK is required for B-cell development and for Ca2+mobilization following B-cell receptor (BCR) engagement (Khan et al.,1995 Immunity 3:283; Genevier et al., 1997 Clin. Exp. Immun., 110:286)where it is believed to be downstream of Src family kinases (such asLyn), Syk & PI3K. BTK has been shown to be important for boththymus-dependent and thymus-independent type 2 responses to antigens(Khan et al., Immunity 1995; 3:283). In mast cells, studies using BTKmouse knock-outs (Hata et al., 1998 J. Exp. Med., 187:1235; Schmidt etal., 2009 Eur. J. Immun., 39:3228) indicate a role for BTK in FcsRIinduced signaling, histamine release & production of cytokines such asTNF, IL-2, & IL-4. In platelets, BTK is important for signaling throughthe glycoprotein VI (GPVI) receptor that responds to collagen and hasbeen shown to promote platelet aggregation and contribute to cytokineproduction from fibroblast-like synoviocytes (Hsu et al., 2013 Immun.Letters 150:97). In monocytes and macrophages, the action of BTK isinvoked in FcγRI induced signaling and may also have role in Toll-LikeReceptor-induced cytokine responses including TLR2, TLR4, TLR8 & TLR9(Horwood et al., 2003 J. Exp. Med., 197:1603; Horwood et al., 2006 J.Immunol., 176:3635; Perez de Diego et al., 2006 Allerg. Clin. Imm.,117:1462; Doyle et al., 2007 J. Biol. Chem., 282:36959, Hasan et al.,2007 Immunology, 123:239; Sochorava et al., 2007 Blood, 109:2553; Lee etal., 2008, J. Biol. Chem., 283:11189).

Therefore, inhibition of BTK is expected to intervene at severalcritical junctions of the inflammatory reactions resulting in aneffective suppression of autoimmune response. As such diseases involvingB-cell receptor activation, antibody-Fc receptor interactions & GPVIreceptor signaling may be modulated by treatment with BTK inhibitors.BTK inhibition is likely to act on both the initiation of autoimmunedisease by blocking BCR signaling and the effector phase by abrogationof FcR signaling on macrophages, neutrophils, basophils, and mast cells.Furthermore, blocking BTK would provide additional benefit viainhibition of osteoclast maturation and therefore attenuate the boneerosions & overall joint destruction associated with rheumatoidarthritis. Inhibiting BTK may be useful in treating a host ofinflammatory and allergic diseases—for example (but not limited to),rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiplesclerosis (MS) and type I hypersensitivity reactions such as allergicrhinitis, allergic conjunctivitis, atopic dermatitis, allergic asthmaand systemic anaphylaxis. For a review on targeting BTK as a treatmentfor inflammatory disorders and autoimmunity as well as leukemias andlymphomas, see Uckun & Qazi 2010 Expert Opin Ther Pat 20:1457. BecauseBTK is highly expressed in cancers of the hematopoietic system &BTK-dependent signaling in believed to be disregulated there, BTKinhibitors are expected to be useful treatments for B-celllymphomas/leukemias & other oncologic disease—for example (but notlimited to) acute lymphoblastic leukemia (ALL), chronic lymphocyticleukemia (CLL), non-Hodgkin's lymphoma (NHL), small lymphocytic lymphoma(SLL), and acute myeloid leukemia (for review, see Buggy & Elias 2012Int Rev Immunol. 31:119). Taken together, BTK inhibitors provide astrong method to treat a host of inflammatory diseases and immunologicaldisorders as well as hematologic cancers.

All kinases bind a common molecule, ATP, and therefore have structurallysimilar binding pockets. Therefore, one of the challenges for any kinaseinhibitor is that they are prone to inhibit more than one kinase due tothe homology of the binding pocket. For example, staurosporine, a wellcharacterized promiscuous kinase inhibitor, has been shown to inhibit atleast 253 with a k_(d) of <3 μM kinases from the human kinome (seeNature Biotechnology, 208, 26, p. 127). Additionally, several marketedkinase inhibitors are known to inhibit more than one intended kinase,for example Imatinib (Gleevec®) targets ABL, ARG, PDGFR-α/β and c-KITkinases, sorafenib (Nexavar®) targets B-RAF, VEGFRs, PDGFR-α/β, FLT3 andc-KIT and sunitinib (Sutent®) targets VEGFR, PDGFR, CSF1R, FLT3 andc-KIT (Nature Reviews Drug Discovery 2011, 10, 111).

Inhibition of certain kinases in the human kinome are known to haveundesired effects when used as pharmaceutical treatment. For instance, anumber of kinase targets have been implicated in playing a role in thecardiotoxicity profiles for kinase inhibitors that are currently on themarket. These kinases can include, but not limited to, VEGFR2, PI3K,AKT, PDGFR-α/p, AMPK, GSK3, ERKs, CDK2, Aurora, PLK, INK, CAMKII<PDK1,mTOR, LKB1, CAMKKP, MEK1/2, PKA, PKCα, RAF1, B-RAF, EGFR, ERBB2, c-Kit,ABL, ARG, JAK2, FAK, DMPK, LTK, ROCK, LKB1, LDB3, PIM, GRK2, GRK5, ASK1,and PTEN (see Nature Reviews Drug Discovery 2011, 10:111). One examplefrom a marketed kinase inhibitor is that in clinical trials withsunitinib, patients were found to be at increased risk for hypertension(see The Lancet 2006, 368:1329; and J. Cin. Oncol. 2009, 27:3584).Subsequent research on the mechanism for the increased hypertensionsuggest that while PDGFR and VEGFR may be playing a role, off-targetkinase inhibition, such as AMPK, may also be contributing to sunitinib'sincreased risk for hypertension (Curr. Hypertens. Rep. 2011, 13:436).Additionally, there is a patent application, US 2011/0212461, that hasbeen filed that is a method for the prediction of cardiotoxicity basedon the activity versus a list of kinases including CSF1R, KIT, FYN,PDGFR beta, FGR, LCK, Ephrin Receptor B2, FRK, ABL1, PDGFR1 alpha, HCK,ABL2, LYN, ZAK, YES1, MAP4K4, PKN1, BRAF, DDR2, MAP4K5 and STK24.Therefore, identification of kinase inhibitors with a selective profileBtk kinase are desirable. The compounds of this invention are selectivefor the inhibition of Btk over other kinases.

Many of the kinases, whether a receptor or non-receptor tyrosine kinaseor a S/T kinase have been found to be involved in cellular signalingpathways involved in numerous pathogenic conditions, includingimmunomodulation, inflammation, or proliferative disorders such ascancer.

Many autoimmune diseases and disease associated with chronicinflammation, as well as acute responses, have been linked to excessiveor unregulated production or activity of one or more cytokines.

The compounds of the invention are also useful in the treatment ofrheumatoid arthritis, asthma, allergic asthma, osteoarthritis, juvenilearthritis, lupus, lupus nephritis, systemic lupus erythematosus (SLE),ankylosing spondylitis, an ocular condition, interstitial cystitis, acancer, a solid tumor, a sarcoma, fibrosarcoma, osteoma, melanoma,retinoblastoma, a rhabdomyosarcoma, glioblastoma, neuroblastoma,teratocarcinoma, hypersensitivity reactions, hyperkinetic movementdisorders, hypersensitivity pneumonitis, hypertension, hypokineticmovement disorders, aordic and peripheral aneuryisms,hypothalamic-pituitary-adrenal axis evaluation, aortic dissection,arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia,spinocerebellar degenerations, streptococcal myositis, structurallesions of the cerebellum, Subacute sclerosing panencephalitis, Syncope,syphilis of the cardiovascular system, systemic anaphalaxis, systemicinflammatory response syndrome, systemic onset juvenile rheumatoidarthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans,transplants, trauma/hemorrhage, type III hypersensitivity reactions,type IV hypersensitivity, unstable angina, uremia, urosepsis, urticaria,valvular heart diseases, varicose veins, vasculitis, venous diseases,venous thrombosis, ventricular fibrillation, viral and fungalinfections, vital encephalitis/aseptic meningitis, vital-associatedhemaphagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease,xenograft rejection of any organ or tissue, heart transplant rejection,hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolyticthrombocytopenic purpura, hemorrhage, idiopathic pulmonary fibrosis,antibody mediated cytotoxicity, Asthenia, infantile spinal muscularatrophy, inflammation of the aorta, influenza A, ionizing radiationexposure, iridocyclitis/uveitis/optic neuritis, juvenile spinal muscularatrophy, lymphoma, myeloma, leukaemia, malignant ascites, hematopoieticcancers, a diabetic condition such as insulin-dependent diabetesmellitus glaucoma, diabetic retinopathy or microangiopathy, sickle cellanaemia, chronic inflammation, glomerulonephritis, graft rejection, Lymedisease, von Hippel Lindau disease, pemphigoid, Paget's disease,fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome,Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthmaor edema following burns, trauma, radiation, stroke, hypoxia, ischemia,ovarian hyperstimulation syndrome, post perfusion syndrome, post pumpsyndrome, post-MI cardiotomy syndrome, preeclampsia, menometrorrhagia,endometriosis, pulmonary hypertension, infantile hemangioma, orinfection by Herpes simplex, Herpes Zoster, human immunodeficiencyvirus, parapoxvirus, protozoa or toxoplasmosis, progressive supranucleopalsy, primary pulmonary hypertension, radiation therapy, Raynaud'sphenomenon, Raynaud's disease, Refsum's disease, regular narrow QRStachycardia, renovascular hypertension, restrictive cardiomyopathy,sarcoma, senile chorea, senile dementia of Lewy body type, shock, skinallograft, skin changes syndrome, ocular or macular edema, ocularneovascular disease, scleritis, radial keratotomy, uveitis, vitritis,myopia, optic pits, chronic retinal detachment, post-laser treatmentcomplications, conjunctivitis, Stargardt's disease, Eales disease,retinopathy, macular degeneration, restenosis, ischemia/reperfusioninjury, ischemic stroke, vascular occlusion, carotid obstructivedisease, ulcerative colitis, inflammatory bowel disease, diabetes,diabetes mellitus, insulin dependent diabetes mellitus, allergicdiseases, dermatitis scleroderma, graft versus host disease, organtransplant rejection (including but not limited to bone marrow and solidorgan rejection), acute or chronic immune disease associated with organtransplantation, sarcoidosis, disseminated intravascular coagulation,Kawasaki's disease, nephrotic syndrome, chronic fatigue syndrome,Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopicvasculitis of the kidneys, chronic active hepatitis, septic shock, toxicshock syndrome, sepsis syndrome, cachexia, infectious diseases,parasitic diseases, acquired immunodeficiency syndrome, acute transversemyelitis, Huntington's chorea, stroke, primary biliary cirrhosis,hemolytic anemia, malignancies, Addison's disease, idiopathic Addison'sdisease, sporadic, polyglandular deficiency type I and polyglandulardeficiency type II, Schmidt's syndrome, adult (acute) respiratorydistress syndrome, alopecia, alopecia areata, seronegative arthopathy,arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative coliticarthropathy, enteropathic synovitis, chlamydia, yersinia and salmonellaassociated arthropathy, atheromatous disease/arteriosclerosis, atopicallergy, autoimmune bullous disease, pemphigus vulgaris, pemphigusfoliaceus, pemphigoid, linear IgA disease, autoimmune haemolyticanaemia, Coombs positive haemolytic anaemia, acquired perniciousanaemia, juvenile pernicious anaemia, peripheral vascular disorders,peritonitis, pernicious anemia, myalgic encephalitis/Royal Free Disease,chronic mucocutaneous candidiasis, giant cell arteritis, primarysclerosing hepatitis, cryptogenic autoimmune hepatitis, AcquiredImmunodeficiency Disease Syndrome, Acquired Immunodeficiency RelatedDiseases, Hepatitis A, Hepatitis B, Hepatitis C, His bundle arrythmias,HIV infection/HIV neuropathy, common varied immunodeficiency (commonvariable hypogammaglobulinaemia), dilated cardiomyopathy, femaleinfertility, ovarian failure, premature ovarian failure, fibrotic lungdisease, chronic wound healing, cryptogenic fibrosing alveolitis,post-inflammatory interstitial lung disease, interstitial pneumonitis,pneumocystis cannii pneumonia, pneumonia, connective tissue diseaseassociated interstitial lung disease, mixed connective tissue disease,associated lung disease, systemic sclerosis associated interstitial lungdisease, rheumatoid arthritis associated interstitial lung disease,systemic lupus erythematosus associated lung disease,dermatomyositis/polymyositis associated lung disease, Sjögren's diseaseassociated lung disease, ankylosing spondylitis associated lung disease,vasculitic diffuse lung disease, haemosiderosis associated lung disease,drug-induced interstitial lung disease, radiation fibrosis,bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocyticinfiltrative lung disease, postinfectious interstitial lung disease,gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis(classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis(anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type Binsulin resistance with acanthosis nigricans, hypoparathyroidism, acuteimmune disease associated with organ transplantation, chronic immunedisease associated with organ transplantation, osteoarthritis, primarysclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathicleucopaenia, autoimmune neutropaenia, renal disease NOS,glomerulonephritides, microscopic vasculitis of the kidneys, Lymedisease, discoid lupus erythematosus, male infertility idiopathic orNOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympatheticophthalmia, pulmonary hypertension secondary to connective tissuedisease, acute and chronic pain (different forms of pain), Goodpasture'ssyndrome, pulmonary manifestation of polyarteritis nodosa, acuterheumatic fever, rheumatoid spondylitis, Still's disease, systemicsclerosis, Sjögren's syndrome, Takayasu's disease/arteritis, autoimmunethrombocytopaenia, toxicity, transplants, and diseases involvinginappropriate vascularization for example diabetic retinopathy,retinopathy of prematurity, choroidal neovascularization due toage-related macular degeneration, and infantile hemangiomas in humanbeings. In addition, such compounds may be useful in the treatment ofdisorders such as ascites, effusions, and exudates, including forexample macular edema, cerebral edema, acute lung injury, adultrespiratory distress syndrome (ARDS), proliferative disorders such asrestenosis, fibrotic disorders such as hepatic cirrhosis andatherosclerosis, mesangial cell proliferative disorders such as diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyndromes, and glomerulopathies, myocardial angiogenesis, coronary andcerebral collaterals, ischemic limb angiogenesis, ischemia/reperfusioninjury, peptic ulcer Helicobacter related diseases, virally-inducedangiogenic disorders, preeclampsia, menometrorrhagia, cat scratch fever,rubeosis, neovascular glaucoma and retinopathies such as thoseassociated with diabetic retinopathy, retinopathy of prematurity, orage-related macular degeneration. In addition, these compounds can beused as active agents against hyperproliferative disorders such asthyroid hyperplasia (especially Grave's disease), and cysts (such ashypervascularity of ovarian stroma characteristic of polycystic ovariansyndrome (Stein-Leventhal syndrome) and polycystic kidney disease sincesuch diseases require a proliferation of blood vessel cells for growthand/or metastasis.

In yet other embodiments, the compounds described herein can be used totreat a cancer, e.g., B-cell proliferative disorders, which include, butare not limited to diffuse large B cell lymphoma, follicular lymphoma,chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cellprolymphocytic leukemia, lymphoplamacytic lymphoma/Waldenstrommacroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma,plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginalzone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large Bcell lymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, Burkitt's lymphoma/leukemia, lymphomatoid granulomatosis,pancreatic cancer, solid or hematological tumors, a benign or malignanttumor, carcinoma of the brain, kidney (e.g., renal cell carcinoma(RCC)), squamous cell carcinoma, salivary gland carcinoma, liver,adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon,rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis,genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma,glioblastomas, neuroblastomas, multiple myeloma or gastrointestinalcancer, especially colon carcinoma or colorectal adenoma or a tumor ofthe neck and head, an epidermal hyperproliferation, psoriasis, prostatehyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma,adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cellcarcinoma, non-small-cell lung carcinoma, lymphomas, (including, forexample, non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (alsotermed Hodgkin's or Hodgkin's disease)), a mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, or a leukemia.

In yet other embodiments, the compounds described herein can be used totreat Behcet's disease, osteoporosis, bone cancer, and bone metastasis,systemic sclerosis, contact dermatitis and other eczematous dermatitis,seborrhoetic dermatitis, lichen planus, epidermolysis bullosa,angiodermas, vasculitides, cutaneous eosinophilias, or vernalconjunctivitis.

In yet other embodiments, the compounds described herein can be used totreat those conditions characterized by inflammation of the nasal mucusmembrane, including acute rhinitis, allergic, atrophic thinitis andchronic rhinitis including rhinitis caseosa, hypertrophic rhinitis,rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa;membranous rhinitis including croupous, fibrinous and pseudomembranousrhinitis and scrofoulous rhinitis, seasonal rhinitis including rhinitisnervosa (hay fever) and vasomotor rhinitis, sarcoidosis, farmer's lungand related diseases, fibroid lung, and idiopathic interstitialpneumonia.

Compounds of Formula (I) of the invention can be used alone or incombination with an additional agent, e.g., a therapeutic agent, saidadditional agent being selected by the skilled artisan for its intendedpurpose. For example, the additional agent can be a therapeutic agentart-recognized as being useful to treat the disease or condition beingtreated by the compound of the present invention. The additional agentalso can be an agent that imparts a beneficial attribute to thetherapeutic composition e.g., an agent that affects the viscosity of thecomposition.

It should further be understood that the combinations which are to beincluded within this invention are those combinations useful for theirintended purpose. The agents set forth below are illustrative forpurposes and not intended to be limited. The combinations, which arepart of this invention, can be the compounds of the present inventionand at least one additional agent selected from the lists below. Thecombination can also include more than one additional agent, e.g., twoor three additional agents if the combination is such that the formedcomposition can perform its intended function.

Preferred combinations are non-steroidal anti-inflammatory drug(s) alsoreferred to as NSAIDS which include drugs like ibuprofen. Otherpreferred combinations are corticosteroids including prednisolone; thewell known side-effects of steroid use can be reduced or even eliminatedby tapering the steroid dose required when treating patients incombination with the compounds of this invention. Non-limiting examplesof therapeutic agents for rheumatoid arthritis with which a compound ofFormula (I) of the invention can be combined include the following:cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies toor antagonists of other human cytokines or growth factors, for example,TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-15,IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, MMP-13 and PDGF.Compounds of the invention can be combined with antibodies to cellsurface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40,CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA ortheirligandsincluding CD154 (gp39 or CD40L).

Preferred combinations of therapeutic agents may interfere at differentpoints in the autoimmune and subsequent inflammatory cascade; preferredexamples include TNF antagonists like chimeric, humanized or human TNFantibodies, D2E7 (U.S. Pat. No. 6,090,382, HUMIRA™), CA2 (REMICADE™),SIMPONI™ (golimumab), CIMZIA™, ACTEMRA™, CDP 571, and soluble p55 or p75TNF receptors, derivatives, thereof, (p75TNFR1gG (ENBREL™) or p55TNFR1gG(Lenercept), and also TNFα converting enzyme (TACE) inhibitors;similarly IL-1 inhibitors (Interleukin-1-converting enzyme inhibitors,IL-RA etc.) may be effective for the same reason. Other preferredcombinations include Interleukin 11. Yet other preferred combinationsare the other key players of the autoimmune response which may actparallel to, dependent on or in concert with IL-18 function; especiallypreferred are IL-12 antagonists including IL-12 antibodies or solubleIL-12 receptors, or IL-12 binding proteins. It has been shown that IL-12and IL-18 have overlapping but distinct functions and a combination ofantagonists to both may be most effective. Yet another preferredcombination is non-depleting anti-CD4 inhibitors. Yet other preferredcombinations include antagonists of the co-stimulatory pathway CD80(B7.1) or CD86 (B7.2) including antibodies, soluble receptors orantagonistic ligands.

A compound of Formula (I) of the invention may also be combined withagents, such as methotrexate, 6-mercaptopurine, azathioprinesulphasalazine, mesalazine, olsalazine chloroquinine/hydroxychloroquine,pencillamine, aurothiomalate (intramuscular and oral), azathioprine,cochicine, corticosteroids (oral, inhaled and local injection), beta-2adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines(theophylline, aminophylline), cromoglycate, nedocromil, ketotifen,ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolatemofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroidssuch as prednisolone, phosphodiesterase inhibitors, adensosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents, agentswhich interfere with signalling by proinflammatory cytokines such asTNFα or IL-1 (e.g., NIK, IKK, JAK1, JAK2, JAK3, p38 or MAP kinaseinhibitors), IL-1β converting enzyme inhibitors, T-cell signallinginhibitors such as kinase inhibitors, metalloproteinase inhibitors,sulfasalazine, 6-mercaptopurines, angiotensin converting enzymeinhibitors, soluble cytokine receptors and derivatives thereof (e.g.soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG(Enbrel™) and p55TNFRIgG (Lenercept), sIL-1RI, sIL-1RII, sIL-6R),antiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ),celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib,etanercept, infliximab, naproxen, valdecoxib, sulfasalazine,methylprednisolone, meloxicam, methylprednisolone acetate, gold sodiumthiomalate, aspirin, triamcinolone acetonide, propoxyphenenapsylate/apap, folate, nabumetone, diclofenac, piroxicam, etodolac,diclofenac sodium, oxaprozin, oxycodone HCl, hydrocodonebitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra,tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine,acetaminophen, alendronate sodium, prednisolone, morphine sulfate,lidocaine hydrochloride, indomethacin, glucosamine sulf/chondroitin,amitriptyline HCl, sulfadiazine, oxycodone HCl/acetaminophen,olopatadine HCl misoprostol, naproxen sodium, omeprazole,cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP,anti-IL-12, Anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740,Roflumilast, IC-485, CDC-801, S1P1 agonists (such as FTY720), PKC familyinhibitors (such as Ruboxistaurin or AEB-071) and Mesopram. Preferredcombinations include methotrexate or leflunomide and in moderate orsevere rheumatoid arthritis cases, cyclosporine and anti-TNF antibodiesas noted above.

Non-limiting examples of therapeutic agents for inflammatory boweldisease with which a compound of Formula (I) of the invention can becombined include the following: budenoside; epidermal growth factor;corticosteroids; cyclosporin, sulfasalazine; aminosalicylates;6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors;mesalamine; olsalazine; balsalazide; antioxidants; thromboxaneinhibitors; IL-1 receptor antagonists; anti-IL-1β monoclonal antibodies;anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors;pyridinyl-imidazole compounds; antibodies to or antagonists of otherhuman cytokines or growth factors, for example, TNF, LT, IL-1, IL-2,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, andPDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28,CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate;cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide;NSAIDs, for example, ibuprofen; corticosteroids such as prednisolone;phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents;complement inhibitors; adrenergic agents; agents which interfere withsignalling by proinflammatory cytokines such as TNFα or IL-1 (e.g. NIK,IKK, p38 or MAP kinase inhibitors); IL-1β converting enzyme inhibitors;TNFα converting enzyme inhibitors; T-cell signalling inhibitors such askinase inhibitors; metalloproteinase inhibitors; sulfasalazine;azathioprine; 6-mercaptopurines; angiotensin converting enzymeinhibitors; soluble cytokine receptors and derivatives thereof (e.g.soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) andantiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ).Preferred examples of therapeutic agents for Crohn's disease with whicha compound of Formula (I) can be combined include the following: TNFantagonists, for example, anti-TNF antibodies, D2E7 (U.S. Pat. No.6,090,382, HUMIRA™), CA2 (REMICADE™), CDP 571, TNFR-Ig constructs,(p75TNFRIgG (ENBREL™) and p55TNFRIgG (LENERCEPT™) inhibitors and PDE4inhibitors. A compound of Formula (I) can be combined withcorticosteroids, for example, budenoside and dexamethasone;sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents whichinterfere with synthesis or action of proinflammatory cytokines such asIL-1, for example, IL-1β converting enzyme inhibitors and IL-1ra; T cellsignaling inhibitors, for example, tyrosine kinase inhibitors;6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine;mercaptopurine; infliximab; methylprednisolone sodium succinate;diphenoxylate/atrop sulfate; loperamide hydrochloride; methotrexate;omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodonebitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole; thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis withwhich a compound of Formula (I) can be combined include the following:corticosteroids; prednisolone; methylprednisolone; azathioprine;cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine;tizanidine; interferon-β1a (AVONEX®; Biogen); interferon-β1b(BETASERON®; Chiron/Berlex); interferon α-n3) (InterferonSciences/Fujimoto), interferon-α (Alfa Wassermann/J&J), interferonβ1A-IF (Serono/Inhale Therapeutics), Peginterferon α 2b(Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; TevaPharmaceutical Industries, Inc.); hyperbaric oxygen; intravenousimmunoglobulin; cladribine; antibodies to or antagonists of other humancytokines or growth factors and their receptors, for example, TNF, LT,IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-I,GM-CSF, FGF, and PDGF. A compound of Formula (I) can be combined withantibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19,CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or theirligands. A compound of Formula (I) may also be combined with agents suchas methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil,leflunomide, an S1P1 agonist, NSAIDs, for example, ibuprofen,corticosteroids such as prednisolone, phosphodiesterase inhibitors,adensosine agonists, antithrombotic agents, complement inhibitors,adrenergic agents, agents which interfere with signalling byproinflammatory cytokines such as TNFαl or IL-1 (e.g., NIK, IKK, p38 orMAP kinase inhibitors), IL-1β converting enzyme inhibitors, TACEinhibitors, T-cell signaling inhibitors such as kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, azathioprine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines(e.g. IL-4, IL-10, IL-13 and TGFβ).

Preferred examples of therapeutic agents for multiple sclerosis in whicha compound of Formula (I) can be combined to include interferon-β, forexample, IFNβ1a and IFNβ1b; copaxone, corticosteroids, caspaseinhibitors, for example inhibitors of caspase-1, IL-1 inhibitors, TNFinhibitors, and antibodies to CD40 ligand and CD80.

A compound of Formula (I) may also be combined with agents, such asalemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliprodenhydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol,α-immunokine NNSO3, ABR-215062, AnergiX. MS, chemokine receptorantagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulatedmitoxantrone), THC. CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidoneallotrap 1258 (RDP-1258), sTNF-R¹, talampanel, teriflunomide, TGF-beta2,tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler,Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitiswith which a compound of Formula (I) can be combined include thefollowing: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam,indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine,methotrexate, azathioprine, minocyclin, prednisone, and anti-TNFantibodies, D2E7 (U.S. Pat. No. 6,090,382; HUMIRA™), CA2 (REMICADE™),CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBREL™) and p55TNFRIgG(LENERCEPT™).

Non-limiting examples of therapeutic agents for asthma with which acompound of Formula (I) can be combined include the following:albuterol, salmeterol/fluticasone, montelukast sodium, fluticasonepropionate, budesonide, prednisone, salmeterol xinafoate, levalbuterolHCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate,triamcinolone acetonide, beclomethasone dipropionate, ipratropiumbromide, azithromycin, pirbuterol acetate, prednisolone, theophyllineanhydrous, methylprednisolone sodium succinate, clarithromycin,zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillintrihydrate, flunisolide, allergy injection, cromolyn sodium,fexofenadine hydrochloride, flunisolide/menthol,amoxicillin/clavulanate, levofloxacin, inhaler assist device,guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl,doxycycline hyclate, guaifenesin/d-methorphan,p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride,mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin,pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed,phenylephrine/cod/promethazine, codeine/promethazine, cefprozil,dexamethasone, guaifenesin/pseudoephedrine,chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate,epinephrine, methylprednisolone, anti-IL-13 antibody, and metaproterenolsulfate.

Non-limiting examples of therapeutic agents for COPD with which acompound of Formula (I) can be combined include the following: albuterolsulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone,albuterol, salmeterol xinafoate, fluticasone propionate, prednisone,theophylline anhydrous, methylprednisolone sodium succinate, montelukastsodium, budesonide, formoterol fumarate, triamcinolone acetonide,levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate,levalbuterol HCl, flunisolide, ceftriaxone sodium, amoxicillintrihydrate, gatifloxacin, zafirlukast, amoxicillin/clavulanate,flunisolide/menthol, chlorpheniramine/hydrocodone, metaproterenolsulfate, methylprednisolone, mometasone furoate,p-ephedrine/cod/chlorphenir, pirbuterol acetate, p-ephedrine/loratadine,terbutaline sulfate, tiotropium bromide, (R,R)-formoterol, TgAAT,cilomilast and roflumilast.

Non-limiting examples of therapeutic agents for HCV with which acompound of Formula (I) (can be combined include the following:Interferon-alpha-2α, Interferon-alpha-2β, Interferon-alpha con1,Interferon-alpha-n1, pegylated interferon-alpha-2α, pegylatedinterferon-alpha-2β, ribavirin, peginterferon alfa-2b+ribavirin,ursodeoxycholic acid, glycyrrhizic acid, thymalfasin, Maxamine, VX-497and any compounds that are used to treat HCV through intervention withthe following targets: HCV polymerase, HCV protease, HCV helicase, andHCV IRES (internal ribosome entry site).

Non-limiting examples of therapeutic agents for Idiopathic PulmonaryFibrosis with which a compound of Formula (I) (can be combined includethe following: prednisone, azathioprine, albuterol, colchicine,albuterol sulfate, digoxin, gamma interferon, methylprednisolone sodiumsuccinate, lorazepam, furosemide, lisinopril, nitroglycerin,spironolactone, cyclophosphamide, ipratropium bromide, actinomycin d,alteplase, fluticasone propionate, levofloxacin, metaproterenol sulfate,morphine sulfate, oxycodone HCl, potassium chloride, triamcinoloneacetonide, tacrolimus anhydrous, calcium, interferon-alpha,methotrexate, mycophenolate mofetil and interferon-gamma-1β.

Non-limiting examples of therapeutic agents for myocardial infarctionwith which a compound of Formula (I) can be combined include thefollowing: aspirin, nitroglycerin, metoprolol tartrate, enoxaparinsodium, heparin sodium, clopidogrel bisulfate, carvedilol, atenolol,morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril,isosorbide mononitrate, digoxin, furosemide, simvastatin, ramipril,tenecteplase, enalapril maleate, torsemide, retavase, losartanpotassium, quinapril hydrochloride/magnesium carbonate, bumetanide,alteplase, enalaprilat, amiodarone hydrochloride, tirofiban HClIm-hydrate, diltiazem hydrochloride, captopril, irbesartan, valsartan,propranolol hydrochloride, fosinopril sodium, lidocaine hydrochloride,eptifibatide, cefazolin sodium, atropine sulfate, aminocaproic acid,spironolactone, interferon, sotalol hydrochloride, potassium chloride,docusate sodium, dobutamine HCl, alprazolam, pravastatin sodium,atorvastatin calcium, midazolam hydrochloride, meperidine hydrochloride,isosorbide dinitrate, epinephrine, dopamine hydrochloride, bivalirudin,rosuvastatin, ezetimibe/simvastatin, avasimibe, and cariporide.

Non-limiting examples of therapeutic agents for psoriasis with which acompound of Formula (I) can be combined include the following:calcipotriene, clobetasol propionate, triamcinolone acetonide,halobetasol propionate, tazarotene, methotrexate, fluocinonide,betamethasone diprop augmented, fluocinolone acetonide, acitretin, tarshampoo, betamethasone valerate, mometasone furoate, ketoconazole,pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea,betamethasone, clobetasol propionate/emoll, fluticasone propionate,azithromycin, hydrocortisone, moisturizing formula, folic acid,desonide, pimecrolimus, coal tar, diflorasone diacetate, etanerceptfolate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor,methylprednisolone acetate, prednisone, sunscreen, halcinonide,salicylic acid, anthralin, clocortolone pivalate, coal extract, coaltar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone,diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/nalact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen,salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib,infliximab, cyclosporine, alefacept, efalizumab, tacrolimus,pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 and ustekinamab.

Non-limiting examples of therapeutic agents for psoriatic arthritis withwhich a compound of Formula (I) can be combined include the following:methotrexate, etanercept, rofecoxib, celecoxib, folic acid,sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (U.S. Pat. No.6,090,382, HUMIRA™), and efalizumab.

Non-limiting examples of therapeutic agents for restenosis with which acompound of Formula (I) can be combined include the following:sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578, andacetaminophen.

Non-limiting examples of therapeutic agents for sciatica with which acompound of Formula (I) can be combined include the following:hydrocodone bitartrate/apap, rofecoxib, cyclobenzaprine HCl,methylprednisolone, naproxen, ibuprofen, oxycodone HCl/acetaminophen,celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeinephosphate/apap, tramadol HCl/acetaminophen, metaxalone, meloxicam,methocarbamol, lidocaine hydrochloride, diclofenac sodium, gabapentin,dexamethasone, carisoprodol, ketorolac tromethamine, indomethacin,acetaminophen, diazepam, nabumetone, oxycodone HCl, tizanidine HCl,diclofenac sodium/misoprostol, propoxyphene n-pap, asa/oxycod/oxycodoneter, ibuprofen/hydrocodone bit, tramadol HCl, etodolac, propoxypheneHCl, amitriptyline HCl, carisoprodol/codeine phos/asa, morphine sulfate,multivitamins, naproxen sodium, orphenadrine citrate, and temazepam.

Preferred examples of therapeutic agents for SLE (Lupus) with which acompound of Formula (I) can be combined include the following: NSAIDS,for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin;COX2 inhibitors, for example, celecoxib, rofecoxib, valdecoxib;anti-malarials, for example, hydroxychloroquine; steroids, for example,prednisone, prednisolone, budenoside, dexamethasone; cytotoxics, forexample, azathioprine, cyclophosphamide, mycophenolate mofetil,methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, forexample Cellcept®. A compound of Formula (I) may also be combined withagents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran®and agents which interfere with synthesis, production or action ofproinflammatory cytokines such as IL-1, for example, caspase inhibitorslike IL-1β converting enzyme inhibitors and IL-1ra. A compound ofFormula (I) may also be used with T cell signaling inhibitors, forexample, tyrosine kinase inhibitors; or molecules that target T cellactivation molecules, for example, CTLA-4-IgG or anti-B7 familyantibodies, anti-PD-1 family antibodies. A compound of Formula (I) (canbe combined with IL-11 or anti-cytokine antibodies, for example,fonotolizumab (anti-IFNg antibody), or anti-receptor receptorantibodies, for example, anti-IL-6 receptor antibody and antibodies toB-cell surface molecules. A compound of Formula (I) may also be usedwith LJP 394 (abetimus), agents that deplete or inactivate B-cells, forexample, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BySantibody), TNF antagonists, for example, anti-TNF antibodies, D2E7 (U.S.Pat. No. 6,090,382; HUMIRA™), CA2 (REMICADE™), CDP 571, TNFR-Igconstructs, (p75TNFRIgG (ENBREL™) and p55TNFRIgG (LENERCEPT™)

In this invention, the following definitions are applicable:

A “therapeutically effective amount” is an amount of a compound ofFormula (I) or a combination of two or more such compounds, whichinhibits, totally or partially, the progression of the condition oralleviates, at least partially, one or more symptoms of the condition. Atherapeutically effective amount can also be an amount which isprophylactically effective. The amount which is therapeuticallyeffective will depend upon the patient's size and gender, the conditionto be treated, the severity of the condition and the result sought. Fora given patient, a therapeutically effective amount can be determined bymethods known to those of skill in the art.

“Pharmaceutically acceptable salts” refers to those salts which retainthe biological effectiveness and properties of the free bases and whichare obtained by reaction with inorganic acids, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acidor organic acids such as sulfonic acid, carboxylic acid, organicphosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinicacid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g. (+)or (−)-tartaric acid or mixtures thereof), amino acids (e.g. (+) or(−)-amino acids or mixtures thereof), and the like. These salts can beprepared by methods known to those skilled in the art.

Certain compounds of Formula (I) which have acidic substituents mayexist as salts with pharmaceutically acceptable bases. The presentinvention includes such salts. Examples of such salts include sodiumsalts, potassium salts, lysine salts and arginine salts. These salts maybe prepared by methods known to those skilled in the art.

Certain compounds of Formula (I) and their salts may exist in more thanone crystal form and the present invention includes each crystal formand mixtures thereof.

Certain compounds of Formula (I) and their salts may also exist in theform of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

Certain compounds of Formula (I) may contain one or more chiral centers,and exist in different optically active forms. When compounds of Formula(I) contain one chiral center, the compounds exist in two enantiomericforms and the present invention includes both enantiomers and mixturesof enantiomers, such as racemic mixtures. The enantiomers may beresolved by methods known to those skilled in the art, for example byformation of diastereoisomeric salts which may be separated, forexample, by crystallization; formation of diastereoisomeric derivativesor complexes which may be separated, for example, by crystallization,gas-liquid or liquid chromatography; selective reaction of oneenantiomer with an enantiomer-specific reagent, for example enzymaticesterification; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support for example silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where the desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step is required to liberate the desired enantiomeric form.Alternatively, specific enantiomers may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting one enantiomer into the other by asymmetrictransformation.

When a compound of Formula (I) contains more than one chiral center, itmay exist in diastereoisomeric forms. The diastereoisomeric compoundsmay be separated by methods known to those skilled in the art, forexample chromatography or crystallization and the individual enantiomersmay be separated as described above. The present invention includes eachdiastereoisomer of compounds of Formula (I) (and mixtures thereof.

Certain compounds of Formula (I) may exist in different tautomeric formsor as different geometric isomers, and the present invention includeseach tautomer and/or geometric isomer of compounds of Formula (I) andmixtures thereof.

Certain compounds of Formula (I) may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers.

The present invention includes each conformational isomer of compoundsof Formula (I) and mixtures thereof.

Certain compounds of Formula (I) may exist in zwitterionic form and thepresent invention includes each zwitterionic form of compounds ofFormula (I) (and mixtures thereof.

As used herein the term “pro-drug” refers to an agent which is convertedinto the parent drug in vivo by some physiological chemical process(e.g., a prodrug on being brought to the physiological pH is convertedto the desired drug form). Pro-drugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent drug is not. The pro-drug may also have improved solubility inpharmacological compositions over the parent drug. An example, withoutlimitation, of a pro-drug would be a compound of the present inventionwherein it is administered as an ester (the “pro-drug”) to facilitatetransmittal across a cell membrane where water solubility is notbeneficial, but then it is metabolically hydrolyzed to the carboxylicacid once inside the cell where water solubility is beneficial.

Pro-drugs have many useful properties. For example, a pro-drug may bemore water soluble than the ultimate drug, thereby facilitatingintravenous administration of the drug. A pro-drug may also have ahigher level of oral bioavailability than the ultimate drug. Afteradministration, the prodrug is enzymatically or chemically cleaved todeliver the ultimate drug in the blood or tissue.

Exemplary pro-drugs upon cleavage release the corresponding free acid,and such hydrolyzable ester-forming residues of the compounds of thisinvention include but are not limited to carboxylic acid substituentswherein the free hydrogen is replaced by (C₁-C₄)alkyl,(C₁-C₁₂)alkanoyloxymethyl, (C₄-C₉)1-(alkanoyloxy)ethyl,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, NN-di(C₁-C₂)-alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Other exemplary pro-drugs release an alcohol of Formula (I) wherein thefree hydrogen of the hydroxyl substituent (e.g., R¹ contains hydroxyl)is replaced by (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₁₂)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylamino-methyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₂-C₄)alkanoyl, arylactyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl wherein said α-aminoacyl moieties areindependently any of the naturally occurring L-amino acids found inproteins, P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radicalresulting from detachment of the hydroxyl of the hemiacetal of acarbohydrate).

As used herein, the term “bridged (C₅-C₁₂) cycloalkyl group” means asaturated or unsaturated, bicyclic or polycyclic bridged hydrocarbongroup having two or three C₃-C₁₀ cycloalkyl rings. Non bridgedcycloalkyls are excluded. Bridged cyclic hydrocarbon may include, suchas bicyclo[2.1.1]hexyl, bicyclo[2.2.I]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl, bomyl,bornenyl, norbornyl, norbomenyl, 6,6-dimethylbicyclo [3.1.1]heptyl,tricyclobutyl, and adamantyl.

As used herein the term “bridged (C₂-C₁₀) heterocyclyl” means bicyclicor polycyclic aza-bridged hydrocarbon groups and may includeazanorbomyl, quinuclidinyl, isoquinuclidinyl, tropanyl,azabicyclo[3.2.1]octanyl, azabicyclo[2.2.1]heptanyl,2-azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl,azabicyclo[3.2.2]nonanyl, azabicyclo[3.3.0]nonanyl, and azabicyclo[3.3.1]nonanyl.

The term “heterocyclic,” “heterocyclyl” or “heterocyclylene,” as usedherein, include non-aromatic, ring systems, including, but not limitedto, monocyclic, bicyclic, tricyclic and spirocyclic rings, which can becompletely saturated or which can contain one or more units ofunsaturation, for the avoidance of doubt, the degree of unsaturationdoes not result in an aromatic ring system) and have 5 to 12 atomsincluding at least one heteroatom, such as nitrogen, oxygen, or sulfur.For purposes of exemplification, which should not be construed aslimiting the scope of this invention, the following are examples ofheterocyclic rings: azepinyl, azetidinyl, indolinyl, isoindolinyl,morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, quinucludinyl,thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl,tetrahydroindolyl, thiomorpholinyl and tropanyl.

The term “heteroaryl” or “heteroarylene” as used herein, includearomatic ring systems, including, but not limited to, monocyclic,bicyclic and tricyclic rings, and have 5 to 12 atoms including at leastone heteroatom, such as nitrogen, oxygen, or sulfur. For purposes ofexemplification, which should not be construed as limiting the scope ofthis invention: azaindolyl, benzo(b)thienyl, benzimidazolyl,benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl,indazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, purinyl,pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl,pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl,quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrazolyl,thiadiazolyl, thienyl, 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazinyl,6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazinyl,1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine,3H-3,4,6,8a-tetraaza-asindacenyl,3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazinyl,pyrazolo[3,4-d]pyrrolo[2,3-b]pyridinyl,1,6-dihydro-1,2,5,6-tetraza-as-indacenyl, 3H-3,4,8a-triaza-as-indacenyl,6H-3-oxa-2,5,6-triaza-as-indacenyl,3,6-dihydro-2,3,6-tetraaza-as-indacenyl,1,6-dihydro-dipyrrolo[2,3-b;2′3′-d]pyridinyl,6H-3-thia-2,5,6-triaza-as-indacenyl or1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine.

As used herein, “alkyl,” “alkylene” or notations such as “(C₁-C₈)”include straight chained or branched hydrocarbons which are completelysaturated. Examples of alkyls are methyl, ethyl, propyl, isopropyl,butyl, pentyl, hexyl and isomers thereof. As used herein, “alkenyl,”“alkenylene,” “alkynylene” and “alkynyl” means C₂-C₈ and includesstraight chained or branched hydrocarbons which contain one or moreunits of unsaturation, one or more double bonds for alkenyl and one ormore triple bonds for alkynyl.

As used herein, “aromatic” groups (or “aryl” or “arylene” groups)include aromatic carbocyclic ring systems (e.g. phenyl) and fusedpolycyclic aromatic ring systems (e.g. naphthyl, biphenyl and1,2,3,4-tetrahydronaphthyl).

As used herein, “cycloalkyl” or “cycloalkylene” means C₃-C₁₂ monocyclicor multicyclic (e.g., bicyclic, tricyclic, spirocyclic, etc.)hydrocarbons that is completely saturated. Examples of a cycloalkylgroup are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, “cycloalkenyl” means C₃-C₁₂ monocyclic or multicyclic(e.g., bicyclic, tricyclic, spirocyclic, etc.) hydrocarbons that has oneor more unsaturated bonds but does not amount to an aromatic group.Examples of a cycloalklenyl group are cyclopentenyl and cyclohexenyl.

As used herein, many moieties or substituents are termed as being either“substituted” or “optionally substituted”. When a moiety is modified byone of these terms, unless otherwise noted, it denotes that any portionof the moiety that is known to one skilled in the art as being availablefor substitution can be substituted, which includes one or moresubstituents, where if more than one substituent then each substituentis independently selected. Such means for substitution are well-known inthe art and/or taught by the instant disclosure. For purposes ofexemplification, which should not be construed as limiting the scope ofthis invention, some examples of groups that are substituents are:(C₁-C₈)alkyl groups, (C₂-C₈)alkenyl groups, (C₂-C₈)alkynyl groups,(C₃-C₁₀)cycloalkyl groups, halogen (F, Cl, Br or I), halogenated(C₁-C₈)alkyl groups (for example but not limited to —CF₃),—O—(C₁-C₈)alkyl groups, ═O, ═CH₂, —OH, —CH₂OH, —CH₂NH₂, (C₂-C₄)alkyl-OH,—CH₂CH₂OCH₂CH₃, —S—(C₁ —C₈)alkyl groups, —SH, —NH(C₁-C₈)alkyl groups,—N((C₁-C₈)alkyl)₂ groups, —NH₂, —C(O)NH₂, —CH₂NHC(O)(C₁-C₄)alkyl,—CH₂NHC(O)CH₂Cl, —CH₂NHC(O)CH₂CN, —CH₂NHC(O)CH₂CH₂N(CH₃)₂,—CH₂NHC(O)C(═CH₂)CH₃, —CH₂NHC(O)(C₂-C₄)alkynyl,—CH₂NHC(O)CH₂CH₂-piperidinyl,—(C₁-C₄)alkyl-morpholinyl,—CH₂NHC(O)CH₂O-phenylwherein the phenyl is optionally substituted with halogen,(C₁-C₄)alkoxy, —C(O)(C₁-C₄)alkyl, —C(O)(C₁-C₄)alkoxy, —C(O)N(H)₂,—C(O)N(CH₃)₂, —C(O)(C₁-C₆)heteroaryl, —N(CH₃)₂, —NHC(O)(C₁-C₄)alkyl,—NHC(O)(C₂-C₄)alkenyl, —NHC(O)CH₂CN, —S(O)₂(C₁-C₄)alkyl,—S(O)₂(C₁-C₆)heteroaryl, —S(O)₂(C₁-C₆) (C₁-C₆)heterocyclyl,4-methylpiperazinecarbonyl, —(C₁-C₄)alkylC(O)NH₂, —C(O)NH(C₁-C₈)alkylgroups, —C(O)N((C₁-C₈)alkyl)₂, —C(O)N(H)(C₃-C₈)cycloalkyl groups,—C(O)(C₁-C₄)alkoxy, —NHC(O)H, —NHC(O)(C₁-C₈)alkyl groups,—NHC(O)(C₃-C₈)cycloalkyl groups, —N((C₁-C₈)alkyl)C(O)H,—N((C₁-C₈)alkyl)C(O)(C₁-C₈)alkyl groups, —NHC(O)NH₂,—NHC(O)NH(C₁-C₈)alkyl groups, —N((C₁-C₈)alkyl)C(O)NH₂groups,—NHC(O)N((C₁-C₈)alkyl)₂groups,—N((C₁-C₈)alkyl)C(O)N((C₁-C₈)alkyl)₂groups, —N((C₁-C₈)alkyl)C(O)NH((C₁-C₈)alkyl), —NHCH₂-heteroaryl, benzyl,—OCH₂-heteroaryl, —C(O)H, —C(O)(C₁-C₈)alkyl groups, —CN, —NO₂,—S(O)(C₁-C₈)alkyl groups, —S(O)₂(C₁-C₈)alkyl groups,—S(O)₂N((C₁-C₈)alkyl)₂ groups, —S(O)₂NH(C₁-C₈)alkyl groups,—S(O)₂NH(C₃-C₈)cycloalkyl groups, —S(O)₂NH₂ groups, —NHS(O)₂(C₁-C₈)alkylgroups, —N((C₁-C₈)alkyl)S(O)₂(C₁-C₈)alkyl groups,—(C₁-C₈)alkyl-O—(C₁-C₈)alkyl groups, —O—(C₁-C₈)alkyl-O—(C₁-C₈)alkylgroups, —C(O)OH, —C(O)O(C₁-C₈)alkyl groups, NHOH, NHO(C₁-C₈)alkylgroups, —O-halogenated (C₁-C₈)alkyl groups (for example but not limitedto —OCF₃), —S(O)₂-halogenated (C₁-C₈)alkyl groups (for example but notlimited to —S(O)₂CF₃), —S-halogenated (C₁-C₈)alkyl groups (for examplebut not limited to —SCF₃), —(C₁-C₆)heterocyclyl (for example but notlimited to pyrrolidine, tetrahydrofuran, pyran or morpholine),—(C₁-C₆)heteroaryl (for example but not limited to tetrazole, imidazole,furan, pyrazine or pyrazole), -phenyl, optionally substituted benzyl,—NHC(O)O—(C₁-C₆)alkyl groups, —N((C₁-C₆)alkyl)C(O)O—(C₁-C₆)alkyl groups,—C(═NH)—(C₁-C₆)alkyl groups, —C(═NOH)—(C₁-C₆)alkyl groups, or—C(═N—O—(C₁-C₆)alkyl)-(C₁-C₆)alkyl groups.

The term “kit” as used herein refers to a packaged product comprisingcomponents with which to administer a compound of Formula (I) of theinvention for treatment of an autoimmune disorder. The kit preferablycomprises a box or container that holds the components of the kit. Thebox or container is affixed with a label or a Food and DrugAdministration approved protocol. The box or container holds componentsof the invention which are preferably contained within plastic,polyethylene, polypropylene, ethylene, or propylene vessels. The vesselscan be capped-tubes or bottles. The kit can also include instructionsfor administering a compound of Formula (I).

One or more compounds of this invention can be administered to a humanpatient by themselves or in pharmaceutical compositions where they aremixed with biologically suitable carriers or excipient(s) at doses totreat or ameliorate a disease or condition as described herein. Mixturesof these compounds can also be administered to the patient as a simplemixture or in suitable formulated pharmaceutical compositions. Atherapeutically effective dose refers to that amount of the compound orcompounds sufficient to result in the prevention or attenuation of adisease or condition as described herein. Techniques for formulation andadministration of the compounds of the instant application may be foundin references well known to one of ordinary skill in the art, such as“Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa.,latest edition.

Suitable routes of administration may, for example, include oral,eyedrop, rectal, transmucosal, topical, or intestinal administration;parenteral delivery, including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections.

Alternatively, one may administer the compound in a local rather than asystemic manner, for example, via injection of the compound directlyinto an edematous site, often in a depot or sustained releaseformulation.

Furthermore, one may administer the drug in a targeted drug deliverysystem, for example, in a liposome coated with endothelial cell-specificantibody.

The pharmaceutical compositions of the present invention may bemanufactured in a manner that is itself known, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the presentinvention thus may be formulated in a conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For injection, the agents of the invention may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks' solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants appropriate to the barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compound with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds can be formulated for parenteral administration byinjection, e.g. bolus injection or continuous infusion. Formulations forinjection may be presented in unit dosage form, e.g. in ampoules or inmulti-dose containers, with an added preservative. The compositions maytake such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly or by intramuscular injection). Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

An example of a pharmaceutical carrier for the hydrophobic compounds ofthe invention is a cosolvent system comprising benzyl alcohol, anonpolar surfactant, a water-miscible organic polymer, and an aqueousphase. The cosolvent system may be the VPD co-solvent system. VPD is asolution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactantpolysorbate 80, and 65% w/v polyethylene glycol 300, made up to volumein absolute ethanol. The VPD co-solvent system (VPD:5W) consists of VPDdiluted 1:1 with a 5% dextrose in water solution. This co-solvent systemdissolves hydrophobic compounds well, and itself produces low toxicityupon systemic administration. Naturally, the proportions of a co-solventsystem may be varied considerably without destroying its solubility andtoxicity characteristics. Furthermore, the identity of the co-solventcomponents may be varied: for example, other low-toxicity nonpolarsurfactants may be used instead of polysorbate 80; the fraction size ofpolyethylene glycol may be varied; other biocompatible polymers mayreplace polyethylene glycol, e.g. polyvinyl pyrrolidone; and othersugars or polysaccharides may substitute for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Certainorganic solvents such as dimethysulfoxide also may be employed, althoughusually at the cost of greater toxicity. Additionally, the compounds maybe delivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials have been established and are wellknown by those skilled in the art. Sustained-release capsules may,depending on their chemical nature, release the compounds for a fewweeks up to over 100 days. Depending on the chemical nature and thebiological stability of the therapeutic reagent, additional strategiesfor protein stabilization may be employed.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

Many of the compounds of the invention may be provided as salts withpharmaceutically compatible counter ions. Pharmaceutically compatiblesalts may be formed with many acids, including but not limited tohydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.Salts tend to be more soluble in aqueous or other protonic solvents thanare the corresponding free base forms.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in aneffective amount to achieve its intended purpose. More specifically, atherapeutically effective amount means an amount effective to preventdevelopment of or to alleviate the existing symptoms of the subjectbeing treated. Determination of the effective amounts is well within thecapability of those skilled in the art.

For any compound used in a method of the present invention, thetherapeutically effective dose can be estimated initially from cellularassays. For example, a dose can be formulated in cellular and animalmodels to achieve a circulating concentration range that includes theIC₅₀ as determined in cellular assays (e.g., the concentration of thetest compound which achieves a half-maximal inhibition of a givenprotein kinase activity). In some cases it is appropriate to determinethe IC₅₀ in the presence of 3 to 5% serum albumin since such adetermination approximates the binding effects of plasma protein on thecompound. Such information can be used to more accurately determineuseful doses in humans. Further, the most preferred compounds forsystemic administration effectively inhibit protein kinase signaling inintact cells at levels that are safely achievable in plasma.

A therapeutically effective dose refers to that amount of the compoundthat results in amelioration of symptoms in a patient. Toxicity andtherapeutic efficacy of such compounds can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the maximum tolerated dose (MTD) and the EDo(effective dose for 50% maximal response). The dose ratio between toxicand therapeutic effects is the therapeutic index and it can be expressedas the ratio between MTD and ED₅₀. Compounds which exhibit hightherapeutic indices are preferred. The data obtained from these cellculture assays and animal studies can be used in formulating a range ofdosage for use in humans. The dosage of such compounds lies preferablywithin a range of circulating concentrations that include the EDo withlittle or no toxicity. The dosage may vary within this range dependingupon the dosage form employed and the route of administration utilized.The exact formulation, route of administration and dosage can be chosenby the individual physician in view of the patient's condition (see,e.g., Fingl et al., 1975, in The Pharmacological Basis of Therapeutics,Ch. 1, p. 1). In the treatment of crises, the administration of an acutebolus or an infusion approaching the MTD may be required to obtain arapid response.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain thekinase modulating effects, or minimal effective concentration (MEC). TheMEC will vary for each compound but can be estimated from in vitro data;e.g. the concentration necessary to achieve 50-90% inhibition of proteinkinase using the assays described herein. Dosages necessary to achievethe MEC will depend on individual characteristics and route ofadministration. However, HPLC assays or bioassays can be used todetermine plasma concentrations.

Dosage intervals can also be determined using the MEC value. Compoundsshould be administered using a regimen which maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90% until the desired amelioration of symptoms isachieved. In cases of local administration or selective uptake, theeffective local concentration of the drug may not be related to plasmaconcentration.

The amount of composition administered will, of course, be dependent onthe subject being treated, on the subject's weight, the severity of theaffliction, the manner of administration and the judgment of theprescribing physician.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. Compositions comprisinga compound of the invention formulated in a compatible pharmaceuticalcarrier may also be prepared, placed in an appropriate container, andlabelled for treatment of an indicated condition.

In some formulations it may be beneficial to use the compounds of thepresent invention in the form of particles of very small size, forexample as obtained by fluid energy milling.

The use of compounds of the present invention in the manufacture ofpharmaceutical compositions is illustrated by the following description.In this description the term “active compound” denotes any compound ofthe invention but particularly any compound which is the final productof one of the following Examples.

a) Capsules

In the preparation of capsules, 10 parts by weight of active compoundand 240 parts by weight of lactose can be de-aggregated and blended. Themixture can be filled into hard gelatin capsules, each capsulecontaining a unit dose or part of a unit dose of active compound.

b) Tablets

Tablets can be prepared, for example, from the following ingredients.

Parts by weight

Active compound 10 Lactose 190 Maize starch 22 Polyvinylpyrrolidone 10Magnesium stearate 3

The active compound, the lactose and some of the starch can bede-aggregated, blended and the resulting mixture can be granulated witha solution of the polyvinylpyrrolidone in ethanol. The dry granulate canbe blended with the magnesium stearate and the rest of the starch. Themixture is then compressed in a tabletting machine to give tablets eachcontaining a unit dose or a part of a unit dose of active compound.

c) Enteric Coated Tablets

Tablets can be prepared by the method described in (b) above. Thetablets can be enteric coated in a conventional manner using a solutionof 20% cellulose acetate phthalate and 3% diethyl phthalate inethanol:dichloromethane (1:1).

d) Suppositories

In the preparation of suppositories, for example, 100 parts by weight ofactive compound can be incorporated in 1300 parts by weight oftriglyceride suppository base and the mixture formed into suppositorieseach containing a therapeutically effective amount of active ingredient.

In the compositions of the present invention the active compound may, ifdesired, be associated with other compatible pharmacologically activeingredients. For example, the compounds of this invention can beadministered in combination with another therapeutic agent that is knownto treat a disease or condition described herein. For example, with oneor more additional pharmaceutical agents that inhibit or prevent theproduction of VEGF or angiopoietins, attenuate intracellular responsesto VEGF or angiopoietins, block intracellular signal transduction,inhibit vascular hyperpermeability, reduce inflammation, or inhibit orprevent the formation of edema or neovascularization. The compounds ofthe invention can be administered prior to, subsequent to orsimultaneously with the additional pharmaceutical agent, whichevercourse of administration is appropriate. The additional pharmaceuticalagents include, but are not limited to, anti-edemic steroids, NSAIDS,ras inhibitors, anti-TNF agents, anti-IL1 agents, antihistamines,PAF-antagonists, COX-1 inhibitors, COX-2 inhibitors, NO synthaseinhibitors, Akt/PTB inhibitors, IGF-1R inhibitors, PKC inhibitors, PI3kinase inhibitors, calcineurin inhibitors and immunosuppressants. Thecompounds of the invention and the additional pharmaceutical agents acteither additively or synergistically. Thus, the administration of such acombination of substances that inhibit angiogenesis, vascularhyperpermeability and/or inhibit the formation of edema can providegreater relief from the deletrious effects of a hyperproliferativedisorder, angiogenesis, vascular hyperpermeability or edema than theadministration of either substance alone. In the treatment of malignantdisorders combinations with antiproliferative or cytotoxicchemotherapies or radiation are included in the scope of the presentinvention.

The present invention also comprises the use of a compound of Formula(I) as a medicament.

A further aspect of the present invention provides the use of a compoundof Formula (I) or a salt thereof in the manufacture of a medicament fortreating vascular hyperpermeability, angiogenesis-dependent disorders,proliferative diseases and/or disorders of the immune system in mammals,particularly human beings.

The present invention also provides a method of treating vascularhyperpermeability, inappropriate neovascularization, proliferativediseases and/or disorders of the immune system which comprises theadministration of a therapeutically effective amount of a compound ofFormula (I) to a mammal, particularly a human being, in need thereof.

Abbreviations

-   Ac Acetyl-   AcOH Glacial acetic acid-   Bn Benzyl-   BnBr Benzyl bromide-   Boc t-Butoxycarbonyl-   Boc₂O Di-tert-butyl dicarbonate-   BPO Benzoyl peroxide-   br broad-   t-BuOH tert-Butanol-   (CH₂O)_(n) paraformaldehyde-   d Doublet-   dba Dibenzylideneacetone-   DCAD (E)-Bis(4-chlorobenzyl) diazene-1,2-dicarboxylate-   DCE 1,2-Dichloroethane-   DCM Dichloromethane (methylene chloride)-   dd Doublet of doublets-   DIEA N,N-Diisopropylethylamine-   DMA Dimethylacetamide-   DMAP 4-Dimethylaminopyridine-   DME 1,2-Dimethoxyethane-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   dppf 1,1′-Bis(diphenylphosphino)ferrocene-   EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   EDC.HCl N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine    hydrochloride-   equiv Equivalent(s)-   EtOAc Ethyl acetate-   Et₂O Diethyl ether-   EtOH Ethanol-   Fmoc Fluorenylmethyloxycarbonyl-   g Gram(s)-   h Hour(s)-   HATU 4-(3-Acrylamidophenyl)-2-ethyl-1H-indole-7-carboxamide-   HOBt 1H-Benzo[d][1,2,3]triazol-1-ol hydrate-   HPLC High-pressure liquid chromatography-   IPA Isopropyl alcohol-   KHMDS Potassium bis(trimethylsilyl)amide-   KOAc Potassium acetate-   KOt-Bu Potassium tert-butoxide-   LC/MS Liquid chromatography/mass spectrometry-   LDA Lithium diisopropylamide-   LiHMDS Lithium bis(trimethylsilyl)amide-   m Multiplet-   M Molar-   MeCN Acetonitrile-   MeOH Methyl alcohol-   min Minute(s)-   mmol Millimole-   MS Mass spectrometry-   MsCl Methanesulfonyl chloride-   MTBE tert-Butyl methyl ether-   n-Normal (nonbranched)-   N Normal-   NaBH(OAc)₃ Sodium triacetoxyhydroborate-   NaHMDS Sodium bis(trimethylsilyl)amide-   n-BuLi n-Butyl lithium-   NaOt-Bu Sodium tert-butoxide-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NH₄OAc Ammonium acetate-   NMP N-Methylpyrolidinone-   NMR Nuclear magnetic resonance-   Pd₂dba₃ Tris(dibenzylideneacetone)dipalladium(O)-   Pd(OAc)₂ Palladium(II) acetate-   Pet ether petroleum ether-   pH −log[H⁺]-   Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)-   Pd(PPh₃)₂Cl₂ Bis(triphenylphosphine)palladium(II) chloride-   PMB para-Methoxybenzyl-   PPh₃ Triphenylphosphine-   ppm Parts per million-   PrOH Propanol-   psi Pounds per square inch-   PyBOP    ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphonium    hexafluorophosphate(V)-   R_(t) Retention time-   rt Room temperature-   s Singlet-   SEM 2-(Trimethylsilyl)ethoxymethyl-   SEMCl 2-(Trimethylsilyl)ethoxymethyl chloride-   SFC Supercritical fluid chromatography-   SPE Solid phase extraction-   t Triplet-   t-Tertiary-   TBAF tetrabutylammonium fluoride-   TBME tert-Butyl methyl ether-   TBDMS tert-Butyldimethylsilane-   TBSCl tert-Butyldimethylsilyl chloride-   TBTU    2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium    tetrafluoroborate-   TEA Triethylamine-   tert-Tertiary-   tert-Butyl X-Phos    2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   TLC Thin layer chromatography-   TMS Trimethylsilyl-   TMSCl Trimethylsilyl chloride-   TMSI Trimethylsilyl iodide-   TsCl p-Toluenesulfonyl chloride-   UV Ultraviolet-   wt % Weight percent-   X-Phos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

General Synthetic Schemes

Compounds of the invention may be prepared using the synthetictransformations illustrated in Schemes I-XVIII. Starting materials arecommercially available, may be prepared by the procedures describedherein, by literature procedures, or by procedures that would be wellknown to one skilled in the art of organic chemistry.

Methods for preparing 1H-indole-7-carboxamide compounds 9 of theinvention are illustrated in Scheme I. In Scheme I, step a, commerciallyavailable 4-bromo-2-nitrobenzoic acid 1 is reacted with vinylmagnesiumbromide via a Bartoli indole synthesis using methods known to oneskilled in the art (for example Preparation #1, step A) to give indole2. Indole 2 can be alkylated with methyl iodide (Scheme I, step b) toprovide methyl 1H-indole-7-carboxylate 3 using methods known to oneskilled in the art (for example Preparation #1, step B). The resultingindole 3 may be tosyl (Ts) protected (Scheme I, step c) using conditionssuch as those described in Preparation #1, step C or those described inGreene, T. W. and Wuts, P. G. M. “Protective Groups in OrganicSynthesis, 3rd Edition”, 1999, Wiley-Interscience; Larock, R. C.“Comprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2^(nd) edition”, 1999, Wiley-VCH. In step d, directedlithiation of methyl 4-bromo-1-tosyl-1H-indole-7-carboxylate 4 followedby trapping of the anion with iodine yields methyl4-bromo-2-iodo-1H-indole-7-carboxylates 5 using conditions such as thosedescribed in Preparation #1 step D. Tosyl protected methyl4-bromo-2-iodo-1H-indole-7-carboxylates 5 may be hydrolyzed anddeprotected under aqueous base conditions in one step e to give4-bromo-2-iodo-1H-indole-7-carboxylic acid 6 using conditions such asthose described in Preparation #1, step E or known to one skilled in theart (for example, the books from Larock, R. C. or Greene, T. W. andWuts, P. G. M. referenced above). In step f,4-bromo-2-iodo-1H-indole-7-carboxylic acid 6 may be converted to aprimary amide 7 as shown using conditions such as those described inGeneral Procedure D. The 4-bromo-2-iodo-1H-indole-7-carboxamide 7 mayundergo a variety of reactions known to one skilled in the art (forexample, Larock, R. C. referenced above) including, but not limited to,Suzuki or Stille coupling reactions such as those described in GeneralProcedure A and Example #22, step A. Alternatively, in step i, the tosylprotected indoles 5 may undergo a variety of reactions known to oneskilled in the art (for example, Larock, R. C. referenced above)including, but not limited to, Suzuki or Stille coupling reactionsdescribed by General Procedure A (for example Preparation #15 step A).Hydrolysis of esters 10 gives acids 11 (Scheme I, step j) using wellknown conditions such as those described in Preparation #15, step B orGeneral Procedure C. In step k, carboxylic acid 11 may be coverted toprimary amides 12 as shown using conditions such as those described inGeneral Procedure D. Removal of the sulfonamide protecting group ofindoles 12 may be accomplished using conditions such as those describedin General Procedure N, or by methods known to one skilled in the art(for example, Larock, R. C. or Greene, T. W. and Wuts, P. G. M.referenced above) to give indoles 8 (Scheme I, step 1). Indoles 8 arereacted with a boronate ester or boronic acid, either commerciallyavailable or prepared by methods known to one skilled in the art (see,for example, Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations, 2^(nd) edition”, 1999, Wiley-VCHor General Procedure P), using Suzuki coupling conditions, such as thosedescribed by General Procedure A, to give 1H-indole-7-carboxamidecompounds 9. Alternatively, in step h, indoles 8 may undergo a varietyof reactions known to one skilled in the art (for example, Larock, R. C.referenced above) including, but not limited to, Buchwald or Negishicoupling conditions as described by General Procedures T and U. Furtherfunctionalization of the R″ group in indoles 9 can be performed, ifdesired, using reactions known to one skilled in the art (for example,Larock, R. C. referenced above). For example, indoles 9 containing adouble bond may be reduced to saturated systems using hydrogenationconditions such as those described in General Procedure L. Ethers can beprepared from indoles 9 containing an alcohol using condition such asthose described in General Procedure Q. In addition amides, ureas,sulfonamides, aryl amines, heteroaryl amines, or sulfonyl ureas can beprepared from indoles 9 containing a primary or secondary amine (forexample General Procedures D, E, I, H, and J). Also, deprotection ofindoles 9 containing a protecting group in either R′ or R″ can beperformed using conditions such as those described in Greene, T. W. andWuts, P. G. M. referenced above or in General Procedures G, M, or N. Forexample, for R″ containing a TBDMS-protected alcohol, the protectinggroup can be removed to yield an unprotected alcohol (for exampleGeneral Procedure M) and the deprotected compounds 9 may then be reactedfurther as described above. Alternatively, compound 4 may first undergoa coupling reaction in step m, including but not limited to, such asSuzuki, Buchwald, or Negishi using conditions as described b GeneralProcedures A, T and U to give compounds 107 followed by an iodinationreaction as illustrated in General Procedure Y to give compounds 108(step n). Indoles 108 may undergo a variety of reactions known to oneskilled in the art (for example, Larock, R. C. referenced above)including, but not limited to, Suzuki or Stille coupling reactions suchas those described in General Procedure A to give compounds 109. One canthen envisage that compounds 109 can undergo hydrolysis, amidation andde-tosylation reactions similar to steps j, k and l to arrive atcompounds 9.

An alternative method preparing 1H-indole-7-carboxamide compounds 9 ofthe invention are illustrated in Scheme II. In step a, indole 3 fromScheme I may be protected with a SEM group using conditions known in theliterature such as those found in Greene, T. W. and Wuts, P. G. M.referenced above or as those described in Preparation #10, step A. Theresulting SEM protected indole 13 can undergo directed lithiationfollowed by trapping of the anion with an electrophile (for exampleiodomethane) yielding indole 14 as shown in step b using conditionsdescribed in Example #19, step A or trapping the anion with iodine asshown in step g yielding methyl4-bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate17 using conditions such as those described in Preparation #10, step B).In step h, indole 14 may undergo a variety of reactions known to oneskilled in the art including, but not limited to, Suzuki or Stillecoupling reactions such as those described in Larock, R. C. referencedabove, General Procedure A, and Preparation #10, step C. Hydrolysis ofesters 14 gives acids 15 (step c) using well known conditions such asthose described in Preparation #10, step D, or General Procedure C.Indole carboxylic acids 15 may be converted to primary amides 16 asshown using conditions such as those described in General Procedure D.The SEM protecting group of 1H-indole-7-carboxamide compounds 16 may beremoved by methods such as those described in Preparation #10, step E orusing conditions such as described in Greene, T. W. and Wuts, P. G. M.referenced above to give 1H-indole-7-carboxamides 8. Indoles 8 may thenbe reacted further as described above (Scheme I) to give the targeted1H-indole-7-carboxamide compounds 9.

An additional method preparing indole-7-carboxamide compounds 9 of theinvention is illustrated in Scheme III. Hydrolysis of ester 17 givesacid 18 (step a) using well known conditions such as those described inPreparation #10, step D or General Procedure C. Acid 18 may be covertedto a primary amide 19 as shown using conditions such as those describedin General Procedure D. The SEM protecting group of indole 19 may beremoved by methods such as those described in Example #19, step D orusing conditions such as described in Greene, T. W. and Wuts, P. G. M.referenced above to give 1H-indole-7-carboxamides 7. Indoles 7 may thenbe reacted further as described above above to give the targeted1H-indole-7-carboxamide compounds 9.

An alternative method preparing 1H-indole-7-carboxamide compounds 9 ofthe invention is illustrated in Scheme IV. Indole 19 may undergo avariety of reactions known to one skilled in the art (for example,Larock, R. C. referenced above) including, but not limited to, Stillecoupling reactions such as those described in Example #22, step A orSuzuki coupling reaction as those described in General Procedure A. Instep b, indole-7-carboxamides 16 are reacted with a boronate ester orboronic acid either commercially available or can be prepared by methodsknown to one skilled in the art (see, for example, Example #22, step B;Larock, R. C. “Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2^(nd) edition”, 1999, Wiley-VCH; orGeneral Procedure A) using Suzuki coupling conditions (for example,Example #19 or General Procedure A). The SEM protecting group of indoles20 may be removed by methods such as those described in Example #22,step D or using conditions such as described in Greene, T. W. and Wuts,P. G. M. referenced above to give 1H-indole-7-carboxamides 9. Indoles 9may then be reacted further as described above.

Indole-7-carboxamide compounds 9 of the invention can also be preparedusing the route illustrated in Scheme V. In step a, methyl ester 21 isprepared using standard condition such as those described in GeneralProcedure F, or Larock, R. C. referenced above. Enolizable ketones 23react with m-nitroaniline 22 to give 4-nitroindoles 24 (step b) usingstandard conditions such as those described in General Procedure F, orTetrahedron, 2004, 60(2), 347. In step c, acids 24 may be converted toprimary amides 25 as shown using conditions such as those described inGeneral Procedure D or F. Amino indoles 26 are prepared by reduction ofthe nitro group of primary amides 25 using methods known to one skilledin the art (for example, General Procedure F, or Larock, R. C.referenced above). Diazotization of 26 followed by iodination gives 27using standard condition such as those described in General Procedure F,or Larock, R. C. referenced above. In step f, indoles 27 may undergo avariety of reactions known to one skilled in the art (for example,Larock, R. C. referenced above) including, but not limited to, Suzuki,Buchwald, or Negishi coupling conditions as described by GeneralProcedures A, T and U. Indoles 9 may then be reacted further asdescribed above.

Methods for preparing 1H-indole-7-carboxamide compounds 30 of theinvention are illustrated in Scheme VI. In Scheme VI, step a,commercially available 4-bromo-1H-indole-7-carbonitrile [Sinova] 28 ishydrolyzed to give primary amide 29 using conditions such as thosedescribed in Preparation #2 or known to one skilled in the art (forexample, the books from Larock, R. C. or Greene, T. W. and Wuts, P. G.M. referenced above). In step b, indole 29 may undergo a variety ofreactions known to one skilled in the art (for example, Larock, R. C.referenced above) including, but not limited to, Suzuki, Buchwald, orNegishi coupling conditions as described by General Procedures A, T andU. Alternatively, indole 29 can be converted to the boronate ester 31using reactions such as those described in General Procedure P. Indole31 may undergo a Suzuki coupling using conditions such as thosedescribed in General Procedure A or known to one skilled in the art (forexample, Larock, R. C. referenced above). Further functionalization ofthe R′ group in indoles 30 can be performed, if desired, using reactionsknown to one skilled in the art (for example, Larock, R. C. referencedabove). For example, indoles 30 containing a double bond may be reducedto saturated systems using hydrogenation conditions such as thosedescribed in General Procedure L. Ethers can be prepared from indoles 30containing an alcohol using condition such as those described in GeneralProcedure Q. In addition amides, ureas, sulfonamides, aryl amines,heteroaryl amines, or sulfonyl ureas can be prepared from indoles 30with an R′ containing a primary or secondary amine (for example GeneralProcedures D, E, I, H, and J). Also, deprotection of the R′ group in1H-indole-7-carboxamide compounds 30 to yield an unprotected compoundcan be performed using conditions such as those described in Greene, T.W. and Wuts, P. G. M. referenced above or in General Procedures G, M, orN. For example, a protecting group such as a Boc group can be removedfrom a protected amine to yield the unprotected amine (for exampleGeneral Procedure G) and the deprotected compounds 30 may then bereacted further as described above.

Methods for preparing 1H-indole-7-carboxamide compounds 35 of theinvention are illustrated in Scheme VII. Nitration of indole 29 (SchemeVII step a) can be performed using conditions such as those described inPreparation #7, step C or known to one skilled in the art (for example,Larock, R. C. referenced above). In step b, indole 32 may undergo avariety of reactions known to one skilled in the art (for example,Larock, R. C. referenced above) including, but not limited to, Suzuki,Buchwald, or Negishi coupling conditions as described by GeneralProcedures A, T and U. Amino indoles 34 are prepared from the reductionof nitroindoles 33 using methods known to one skilled in the art (forexample, Preparation #7, step E, or Larock, R. C. referenced above). Theamino indoles 34 may be coverted to give amides 35 as shown in step dusing conditions such as those described in General Procedure D or E.

Methods for preparing 1H-pyrrolo[3,2-c]pyridine-7-carboxamides 39 of theinvention are illustrated in Scheme VIII. In Scheme VIII, step a,6-bromo-4-nitronicotinic acid [European Journal of Medicinal Chemistry1977, 12(6), 541] 36 is reacted with vinylmagnesium bromide via aBartoli indole synthesis using methods known to one skilled in the art(for example Preparation #9, step A) to give pyrrolo[3,2-c]pyridine 37.In step b, the acid of compounds 37 may be converted to primary amides38 as shown using conditions such as those described in GeneralProcedure D. Pyrrolo[3,2-c]pyridine 38 may undergo a variety ofreactions known to one skilled in the art (for example, Larock, R. C.referenced above) including, but not limited to, Suzuki, Buchwald, orNegishi coupling conditions as described by General Procedures A, T andU. Further functionalization of the R′ group in pyrrolo[3,2-c]pyridines39 can be performed, if desired, using reactions known to one skilled inthe art (for example, Larock, R. C. referenced above). For example,indoles 39 containing a double bond may be reduced to saturated systemsusing hydrogenation conditions such as those described in GeneralProcedure L. Ethers can be prepared from indoles 39 containing analcohol using condition such as those described in General Procedure Q.In addition amides, ureas, sulfonamides, aryl amines, heteroaryl amines,or sulfonyl ureas can be prepared from indoles 39 containing a primaryor secondary amine (for example General Procedures D, E, I, H, and J).Also, deprotection of indoles 39 containing a protecting group in R′ canbe performed using conditions such as those described in Greene, T. W.and Wuts, P. G. M. referenced above or in General Procedures G, M, or N.For example, for R″ containing a TBDMS-protected alcohol, the protectinggroup can be removed to yield an unprotected alcohol (for exampleGeneral Procedure M) and the deprotected compounds 39 may then bereacted further as described above.

Methods for preparing 1H-pyrrolo[2,3-c]pyridine-7-carboxamides 44 of theinvention are illustrated in Scheme IX. In Scheme IX, step a,5-bromo-2-chloro-3-nitropyridine 40 is reacted with vinylmagnesiumbromide via a Bartoli indole synthesis using methods known to oneskilled in the art (for example, Example #2, step A) to givepyrrolo[2,3-c]pyridine 41. In step b, pyrrolo[2,3-c]pyridine 41 mayundergo a variety of reactions known to one skilled in the art (forexample, Larock, R. C. referenced above) including, but not limited to,Suzuki, Buchwald, or Negishi coupling conditions as described by GeneralProcedures A, T and U to give pyrrolo[2,3-c]pyridines 42. In step c,Pd-mediated carbonylation of pyrrolo[2,3-c]pyridines 42 gives esters 43using methods known to one skilled in the art such as those described inExample #2, step C. Esters 43 may undergo ammonolosis such as thosedescribed in Example #2, step D or known to one skilled in the art (forexample, Larock, R. C. referenced above) give compounds 44. Furtherfunctionalization of the R′ group in pyrrolo[2,3-c]pyridines 44 can beperformed, if desired, using reactions known to one skilled in the art(for example, Larock, R. C. referenced above). For example, indoles 44containing a double bond may be reduced to saturated systems usinghydrogenation conditions such as those described in General Procedure L.Ethers can be prepared from indoles 44 containing an alcohol usingcondition such as those described in General Procedure Q. Also,deprotection of indoles 44 containing a protected alcohol can beperformed using conditions such as those described in Greene, T. W. andWuts, P. G. M. referenced above or in General Procedures M. In additionamides, ureas, sulfonamides, aryl amines, heteroaryl amines, or sulfonylureas can be prepared from indoles 44 with an R′ containing a primary orsecondary amine (for example General Procedures D, E, I, H, and J).Also, deprotection of the R′ group in 1H-indole-7-carboxamide compounds44 to yield an unprotected compound can be performed using conditionssuch as those described in Greene, T. W. and Wuts, P. G. M. referencedabove or in General Procedures G, M, or N. For example, a protectinggroup such as a Boc group can be removed from a protected amine to yieldthe unprotected amine (for example General Procedure G) and thedeprotected compounds 44 may then be reacted further as described above.

Methods for preparing 1H-indole-7-carboxamides 51 of the invention areillustrated in Scheme X. In Scheme X, step a, indole 45 under goes aVilsmeier-Haack reaction using methods known to one skilled in the art(for example, Example #3, step A) to give aldehyde 46. The reductiveamination of aldehyde 46 with 4-methoxybenzylamine (PMB) usingconditions such as those described in General Procedure H gives amine 47(Scheme X, step b). Hydrolysis of ester 47 gives acid 48 (step c) usingwell known conditions such as those described in Example #3, step C orGeneral Procedure C. Acid 48 may be converted to a primary amide 49 asshown using conditions such as those described in General Procedure D.Indole 49 may undergo a variety of reactions known to one skilled in theart (for example, Larock, R. C. referenced above) including, but notlimited to, Suzuki, Buchwald, or Negishi coupling conditions asdescribed by General Procedures A, T and U. Indoles 50 may be convertedto give methyl indoles 51 using conditions such as those described inExample #3, step F.

Methods for preparing1,2,3,6-tetrahydropyrrolo[2,3-e]indole-5-carboxamides 58 of theinvention are illustrated in Scheme XI. Nitration of 5-bromoindoline 52(Scheme XI, step a) can be performed using conditions such as thosedescribed in Example #4, step A or known to one skilled in the art (forexample, Larock, R. C. referenced above). The resulting indoline 53 maybe protected (Scheme XI, step b) using conditions described in Greene,T. W. and Wuts, P. G. M. referenced above (for example, a Boc protectinggroup using conditions such as those described in Example #4, step B orthose described in Greene, T. W. and Wuts, P. G. M. referenced above).In Scheme XI, step c, indoline 54 is reacted with vinylmagnesium bromidevia a Bartoli indole synthesis using methods known to one skilled in theart to give indole 55 using conditions described in Example #4, step C.In step d, Pd-mediated cyanation of bromide 55 gives the correspondingnitrile 56 (for example Example #4, step D or Tetrahedron Letters 1999,40(47), 8193-8195). Subsequent hydrolysis of nitrile 56 gives a primaryamide 57 (Scheme XI, step e) using methods known to one skilled in theart (for example, General Procedure O). The primary amide 57 may beconverted to give amides 58 as shown in step f using conditions such asthose described in General Procedure D or E.

Methods for preparing benzimidazoles 64 of the invention are illustratedin Scheme XII. In step a, 4,7-dibromobenzo[c][1,2,5]thiadiazole 59 mayundergo a variety of reactions known to one skilled in the art (forexample, Larock, R. C. referenced above) including, but not limited to,Suzuki, Buchwald, or Negishi coupling conditions as described by GeneralProcedures A, T and U. In step b, Pd-mediated cyanation of bromide 60gives the corresponding nitriles 61 (for example Tetrahedron Letters1999, 40(47), 8193-8195). Nitriles 61 can undergo ring opening to givediamine 62 using conditions such as those described in Example #14, stepC. As shown in Scheme XII, step d, the cyclization of the diamine 62 canbe accomplished by reacting with aldehydes (for example, Example #14,step D). Hydrolysis of nitrile 63 gives benzimidazoles 64 (Scheme XII,step e) using methods known to one skilled in the art such as thosedescribed in General Procedure O.

Methods for preparing indazoles 70 of the invention are illustrated inScheme XIII. In Scheme XIII, step a, 2-amino-4-chloro-3-methylbenzoicacid [Enamine] 65 is esterified using standard conditions such as thosedescribed in General Procedure F or Larock, R. C. referenced above. Instep b, the cyclization of ester 66 gives indazole 67 using methodsknown to one skilled in the art (for example, Example #18, step B orWO2007/113596). Hydrolysis of ester 67 gives acid 68 (Scheme XIII, stepc) using well known conditions such as those described in GeneralProcedure C. The acid 68 may be coverted to amide 69 as shown in step dusing conditions such as those described in General Procedure D. Indole69 may undergo a variety of reactions known to one skilled in the art(for example, Larock, R. C. referenced above) including, but not limitedto, Suzuki, Buchwald, or Negishi coupling conditions as described byGeneral Procedures A, T and U. Further functionalization of the R′ groupin indoles 70 can be performed, if desired, using reactions known to oneskilled in the art (for example, Larock, R. C. referenced above). Forexample, indoles 70 containing a double bond may be reduced to saturatedsystems using hydrogenation conditions such as those described inGeneral Procedure L. Ethers can be prepared from indoles 70 containingan alcohol using conditions such as those described in General ProcedureQ. In addition amides, ureas, sulfonamides, aryl amines, heteroarylamines, or sulfonyl ureas can be prepared from indoles 70 with an R′containing a primary or secondary amine (for example General ProceduresD, E, I, H, and J). Also, deprotection of the R′ group in1H-indole-7-carboxamide compounds 70 to yield an unprotected compoundcan be performed using conditions such as those described in Greene, T.W. and Wuts, P. G. M. referenced above or in General Procedures G, M, orN. For example, a protecting group such as a Boc group can be removedfrom a protected amine to yield the unprotected amine (for exampleGeneral Procedure G) and the deprotected compounds 70 may then bereacted further as described above.

Methods for preparing 1H-indole-7-carboxamide compounds 77 of theinvention are illustrated in Scheme XIV. In Scheme XIV, step a, indole71 may be tosyl (Ts) protected (Scheme I, step c) using conditions suchas those described in Preparation #1 step C or those described inGreene, T. W. and Wuts, P. G. M. or Larock, R. C. referenced above). Instep b, directed lithiation of 4-fluoro-1-tosyl-1H-indole-7-carbonitrile72 followed by trapping of the anion with iodine yields indole 73 usingconditions such as those described in Preparation #1, step D. The4-fluoro-2-iodo-1-tosyl-1H-indole-7-carbonitrile 73 may undergo avariety of reactions known to one skilled in the art (for example,Larock, R. C. referenced above) including, but not limited to, Suzukicoupling reactions such as those described in General Procedure A.Further functionalization of the R′ group in tosyl protectedcarbonitriles 74 can be performed, if desired, using reactions known toone skilled in the art (for example, Larock, R. C. referenced above).For example, formation of amides, ethers, ureas, sulfonamides, arylamines, heteroaryl amines, or sulfonyl ureas can be prepared fromcompounds 74 with an R′ containing a primary or secondary amine (forexample General Procedures D, E, I, H, and J). Also, deprotection of theR′ group in compounds 74 to yield an unprotected compound can beperformed using conditions such as those described in Greene, T. W. andWuts, P. G. M. referenced above or in General Procedures G, M, or N. Forexample, a protecting group such as a Boc group can be removed from aprotected amine to yield the unprotected amine (for example Preparation#27, Step D or General Procedure G) and the deprotected compounds 74 maythen be reacted further as described above amine. Indole carbonitriles74 shown in step d can be reacted with amines via displacement chemistryusing conditions known to one skilled in the art such as those describedin General Procedure B to give compounds 75. Tosyl protected1H-indole-7-carbonitriles 75 may be deprotected under aqueous baseconditions in one step to give compound 76 using conditions such asthose described in Example #12, step B or known to one skilled in theart (for example, the books from Larock, R. C. or Greene, T. W. andWuts, P. G. M. referenced above). In step f, 1H-indole-7-carbonitriles76 hydrolyzed to give primary amide 77 using conditions such as thosedescribed in Preparation #2 or known to one skilled in the art (forexample, the books from Larock, R. C. or Greene, T. W. and Wuts, P. G.M. referenced above). In addition, amides, carbamates, ureas, orsubstituted amines can be prepared from 1H-indole-7-carboxamidecompounds 77 containing a primary or secondary amine (for exampleGeneral Procedures). Also, deprotection of 1H-indole-7-carboxamidecompounds 77 containing a protected primary or secondary amine can beperformed using conditions such as those described in Greene, T. W. andWuts, P. G. M. referenced above or in General Procedures. For example,for R″ or R′″ containing a protecting group (for example a Boc group),the protecting group can be removed to yield the unprotected amine (forexample General Procedure G) and the deprotected compounds 3 may then bereacted further as described above.

Methods for preparing 7-chlorothiazolo[5,4-c]pyridine-4-carboxamides 87of the invention are illustrated in Scheme XV. Wittig reaction of analdehyde 78 (step a) is performed with a triphenyl phosphonium ylideusing standard conditions known to on skilled in the art, such as thosedescribed in Preparation #46, step A or Larock, R. C. referenced above,to give α, β unsaturated methyl ester 79. This intermediate is reactedwith a boronate or boronic acid via a Suzuki reaction in step b, usingconditions such as those illustrated in Preparation #46, step B.Intermediate 80 is hydrolyzed to give an acid as shown in Preparation#46, step B (step c). In step d, the acid is converted to an acyl azidevia in situ formation of an acyl chloride using standard conditions suchas those described Preparation #46, step D or WO 2012/035039. The acylazide intermediate can then undergo a Curtius rearrangement and cyclizeto give a pyridone 83 in step e, under high temperatures (For example,Preparation #46, step E or WO 2012/035039). On treatment with POCl₃, instep f, pyridine-2-chloride is formed (for example, Preparation #46,step F or WO 2012/035039), which can subsequently be treated with NCS instep g, to afford a 4-bromo-7-chlorothiazolo[5,4-c]pyridine intermediate85, as illustrated in Preparation #46, step G. Conversion of the bromogroup in 85 to a cyano functionality is performed via Pd-catalyzedcyanation reaction and subsequent hydrolysis of the cyano group yields a7-chlorothiazolo[5,4-c]pyridine-4-carboxamide as illustrated inPreparation #46, step H. In step j,thiazolo[5,4-c]pyridine-4-carboxamide 87 may undergo a variety ofreactions known to one skilled in the art (for example, Larock, R. C.referenced above) including, but not limited to, Suzuki, Buchwald, orNegishi coupling conditions as described by General Procedures A, T andU to give thiazolo[5,4-c]pyridine-4-carboxamides 88.

A second alternative for the preparation of1H-pyrrolo[3,2-c]pyridine-7-carboxamides 39 to the route shown in schemeVIII is shown in scheme XVI, wherein1H-pyrrolo[3,2-c]pyridine-7-carboxamides 39 can also be prepared fromcommercially available methyl 1H-pyrrolo[3,2-c]pyridine-7-carboxylate89, which is first tosylated in step a, using standard conditions knownto one skilled in the art, as shown in General Procedure AH. Thetosylated intermediate 90 is then oxidized (step b) using conditionssuch as those described in General Procedure AC to give an N-oxideintermediate 91. In step c the material is halogenated as illustrated inPreparation #45, step C, followed by hydrolysis using a base, to bothremove the tosyl group and hydrolyze the ester to an acid usingconditions such as those described in General Procedure X. The acid canthen undergo a standard amine coupling reaction as illustrated inGeneral Procedure D, to give the amide in step e. Thepyrrolo[3,2-c]pyridine 94 may undergo a variety of reactions known toone skilled in the art (for example, Larock, R. C. referenced above)including, but not limited to, Suzuki, Buchwald, or Negishi couplingconditions as described by General Procedures A, T and U to givecompounds 39. Further functionalization of the R′ group inpyrrolo[3,2-c]pyridines 39 can be performed, if desired, using reactionsknown to one skilled in the art (for example, Larock, R. C. referencedabove). For example, pyrrolo[3,2-c]pyridines 39 containing a double bondmay be reduced to saturated systems using hydrogenation conditions suchas those described in General Procedure L. Ethers can be prepared fromindoles 39 containing an alcohol using condition such as those describedin General Procedure Q. In addition amides, ureas, sulfonamides, arylamines, heteroaryl amines, or sulfonyl ureas can be prepared fromindoles 39 containing a primary or secondary amine (for example GeneralProcedures D, E, I, H, and J). Also, deprotection of indoles 39containing a protecting group in R′ can be performed using conditionssuch as those described in Greene, T. W. and Wuts, P. G. M. referencedabove or in General Procedures G, M, or N. For example, for R″containing a TBDMS-protected alcohol, the protecting group can beremoved to yield an unprotected alcohol (for example General ProcedureM) and the deprotected compounds 39 may then be reacted further asdescribed above.

A third alternative to routes shown in schemes VIII and XVI for thepreparation of 1H-pyrrolo[3,2-c]pyridine-7-carboxamides 39 is shown inscheme XVII. In step a, (4-methoxyphenyl)methanamine is treated withdimethyl 3-oxopentanedioate to give intermediate 96, which is notisolated. In step b, it is cyclized in situ via treatment withchloroacetaldehyde using conditions such as those illustrated inPreparation #37, step A or WO2005121140. De-protonation of the acidichydrogen of 97 and reaction with methylformate, in step c, isaccomplished using methods known to one skilled in the art (for examplePreparation #37, step B, or WO 2005121140) to give intermediate 98. Instep d, cyclization of intermediate 98 is performed using conditionssuch as those illustrated in Preparation #37, step C or WO 2005121140 togive the pyridinone intermediate 99. Subsequent aromatization andhalogenation of pyridinone intermediate 99 in step e is done using wellknown conditions (for example Preparation #37, step D or WO 2005121140)to give pyrrolo[3,2-c]pyridine 100. Hydrolysis of the esterfunctionality in 100 gives acid 93 (step f) using standard conditionssuch as those described in General Procedure C. The acid can thenundergo an amine coupling reaction as illustrated in General ProcedureD, to give the amide in step e. The pyrrolo[3,2-c]pyridine 94 mayundergo a variety of reactions known to one skilled in the art (forexample, Larock, R. C. referenced above) including, but not limited to,Suzuki, Buchwald, or Negishi coupling conditions as described by GeneralProcedures A, T and U to give compounds 39. Further functionalization ofthe R′ group in pyrrolo[3,2-c]pyridines 39 can be performed, if desired,using reactions known to one skilled in the art (for example, Larock, R.C. referenced above). For example, pyrrolo[3,2-c]pyridines 39 containinga double bond may be reduced to saturated systems using hydrogenationconditions such as those described in General Procedure L. Ethers can beprepared from indoles 39 containing an alcohol using condition such asthose described in General Procedure Q. In addition amides, ureas,sulfonamides, aryl amines, heteroaryl amines, or sulfonyl ureas can beprepared from indoles 39 containing a primary or secondary amine (forexample General Procedures D, E, I, H, and J). Also, deprotection ofindoles 39 containing a protecting group in R′ can be performed usingconditions such as those described in Greene, T. W. and Wuts, P. G. M.referenced above or in General Procedures G, M, or N. For example, forR″ containing a TBDMS-protected alcohol, the protecting group can beremoved to yield an unprotected alcohol (for example General ProcedureM) and the deprotected compounds 39 may then be reacted further asdescribed above.

Alternative methods for preparing1H-pyrrolo[2,3-c]pyridine-7-carboxamides 44 of the invention areillustrated in Scheme XVIII. 4-Bromo-1H-pyrrolo[2,3-c]pyridine 101 isoxidized to the N-oxide intermediate using methods known to one skilledin the art (for example General Procedure AC). Cyanation of the N-oxide102 in step b is accomplished using conditions such as those illustratedin General Procedure AD to give the carbonitrile 103. The carbonitrile103 may undergo a variety of reactions known to one skilled in the art(for example, Larock, R. C. referenced above) including, but not limitedto, Suzuki, Buchwald, or Negishi coupling conditions as described byGeneral Procedures A, T and U to give pyrrolo[2,3-c]pyridines 106.Subsequent hydrolysis of pyrrolo[2,3-c]pyridines 106 in step f, usingstandard conditions (for example General Procedure O) will yieldcompounds 44. Alternatively the carbonitrile 103 may first be hydrolyzedas shown in in step c to give the amide 104 when subjected to knownconditions (for example General Procedure O). The amide 104 may thenundergo a variety of reactions known to one skilled in the art (forexample, Larock, R. C. referenced above) including, but not limited to,Suzuki, Buchwald, or Negishi coupling conditions as described by GeneralProcedures A, T and U to give compounds 44. Further functionalization ofthe R′ group in pyrrolo[2,3-c]pyridines 44 can be performed, if desired,using reactions known to one skilled in the art (for example, Larock, R.C. referenced above). For example, pyrrolo[2,3-c]pyridines 44 containinga double bond may be reduced to saturated systems using hydrogenationconditions such as those described in General Procedure L. Ethers can beprepared from pyrrolo[2,3-c]pyridines 44 containing an alcohol usingcondition such as those described in General Procedure Q. In additionamides, ureas, sulfonamides, aryl amines, heteroaryl amines, or sulfonylureas can be prepared from pyrrolo[2,3-c]pyridines 44 containing aprimary or secondary amine (for example General Procedures D, E, I, H,and J). Also, deprotection of pyrrolo[2,3-c]pyridines 44 containing aprotecting group in R′ can be performed using conditions such as thosedescribed in Greene, T. W. and Wuts, P. G. M. referenced above or inGeneral Procedures G, M, or N. For example, for R″ containing aTBDMS-protected alcohol, the protecting group can be removed to yield anunprotected alcohol (for example General Procedure M) and thedeprotected compounds 44 may then be reacted further as described above.

If desired, chiral separation of any of the chiral compounds in SchemesI-XVIII may be done using methods known to one skilled in the art suchas chiral preparative HPLC, chiral SFC or crystallization ofdiastereomeric salts.

GENERAL PROCEDURES AND EXAMPLES

The general synthetic schemes that were utilized to construct themajority of compounds disclosed in this application are described belowin Schemes 1-34. These schemes are provided for illustrative purposesonly and are not to be construed as limiting the scope of the invention.

LIST OF GENERAL PROCEDURES

-   General Procedure A Suzuki Reaction of an aryl or heteroaryl halide    with an aryl or heteroaryl boronic acid or boronate-   General Procedure B Nucleophilic displacement of an aryl halide with    an amine-   General Procedure C Hydrolysis of an ester to a carboxylic acid-   General Procedure D Formation of an amide from an amine and a    carboxylic acid-   General Procedure E Formation of an amide from an amine and an acid    halide or anhydride-   General Procedure F Formation of a 4-iodoindole-7-carboxamide-   General Procedure G Acidic cleavage of a Boc-protected amine-   General Procedure H Reductive amination of an aldehyde or ketone    with a primary or secondary amine-   General Procedure I Formation of a sulfonamide from an amine and a    sulfonyl chloride-   General Procedure J. Substitution of an alkyl halide with an amine    nucleophile-   General Procedure K Hydrolysis of an acetonide-   General Procedure L Hydrogenation of an alkene-   General Procedure M Removal of a silyl group from an O-silyl ether-   General Procedure N Hydrolysis of a sulfonamide-   General Procedure O Hydrolysis of a nitrile to a primary amide-   General Procedure P Formation of a boronate from an aryl halide or    heteroaryl halide-   General Procedure Q Mitsunobu reaction of an alcohol-   General Procedure R Reduction of a nitro group to an amine using Fe-   General Procedure S Demethylation of aryl methyl ether-   General Procedure T Buchwald reaction of an aryl halide or an    heteroaryl halide with an amine-   General Procedure U Negishi cross-coupling reaction of an aryl    halide or a heteroaryl halide with an organozinc-   General Procedure V Formation of an amide from a Boc-protected amine    and a carboxylic acid-   General Procedure W Conversion of a vinyl triflate to a vinyl    boronate or boronic acid-   General Procedure X Hydrolysis of an ester to a carboxylic acid    under basic conditions and removal of a tosyl group from an N-tosyl    protected heteroaryl ring-   General Procedure Y Iodination of a 1H-indole or a 1H-aza indole    ring to give a 2-iodo-1H-indole or a 2-iodo-1H-azaindole ring-   General Procedure Z Formation of an N-Boc protected amine-   General Procedure AA Conversion of a ketone to a vinyl triflate-   General Procedure AB Reduction of a double bond and removal of a CBZ    group from a CBZ protected amine-   General Procedure AC N-Oxidation of an N containing hetero aromatic    ring-   General Procedure AD Cyanation of an N-oxide containing heteroaryl    ring-   General Procedure AE Reduction of an ester to form an alcohol-   General Procedure AF Reduction of a pyridine ring to a piperidine    ring-   General Procedure AG Borylation of a vinyl triflate and Suzuki    reaction of the newly formed boronate with an aryl halide-   General Procedure AH Formation of an N-tosyl protected    heteroaromatic ring

The following examples are ordered according to the final generalprocedure used in their Preparation. The synthetic routes to any novelintermediates are detailed by sequentially listing the general procedure(letter codes) in parentheses after their name with additional reactantsor reagents as appropriate. A worked example of this protocol is givenbelow using Example #A.3.7 as a non-limiting illustration. Example#A.3.7 is2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(4-(difluoromethyl)benzamido)-2-methylphenyl)-1H-indole-7-carboxamide,which was prepared from2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-bromo-1H-indole-7-carboxamideusing General Procedure A with4-(difluoromethyl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamideas represented in Scheme A.

The precursor to Example #A.3.7,2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-bromo-1H-indole-7-carboxamide,was prepared (as shown in Scheme B) by reacting4-bromo-2-iodo-1H-indole-7-carboxamide (Preparation #1) with1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone,commercially available Combi-Blocks, following the conditions given inGeneral Procedure A. Hence the Example #A.3.7 would be written as:Example #A.3.7 was prepared from4-(difluoromethyl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide(Preparation #29) and2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-bromo-1H-indole-7-carboxamide(prepared using A with 4-bromo-2-iodo-1H-indole-7-carboxamide[Preparation #1] and1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone[Combi-Blocks]) using General Procedure A. In the tables after a GeneralProcedure, this is represented by having one reactant in the title ofthe table and one in a separate column in the same row as the product.

In Vitro BTK Kinase Activity Measured by Time-Resolved FluorescenceResonance Energy Transfer

(trFRET) The in-house BTK corresponds to recombinant human catalyticdomain (aa 393-659), which was expressed in SF9 cells with an N-terminalhis tag and purified by immobilized metal affinity chromatography. BTKwas mixed with peptide substrate (biotin-TYRI, Sequence:Biotin-(Ahx)-GAEEEIYAAFFA-COOH, 0.2 μM final) at varying inhibitorconcentrations in reaction buffer: 50 mM MOPSO pH 6.5, 10 mM MgCl₂, 2 mMMnCl₂, 2.5 mM DTT, 0.01% BSA, 0.1 mM Na₃VO₄ and 0.001 mM ATP. Afterabout 60 min incubation at room temperature, the reaction was quenchedby addition of EDTA (final concentration: 100 mM) and developed byaddition of detection reagents (final approximate concentrations: 30 mMHEPES pH 7.0, 0.06% BSA, 0.006% Tween-20, 0.24 M KF, 80 ng/mL PT66K(europium labeled anti-phosphotyrosine antibody cat #61T66KLB Cisbio,Bedford, Mass.) and 0.6 g/mL SAXL (Phycolinkstreptavidin-allophycocyanin acceptor, cat #PJ25S, Prozyme, San Leandro,Calif.). The developed reaction was incubated in the dark for about 60min at room temperature, then read via a time-resolved fluorescencedetector (Rubystar, BMG) using a 337 nm laser for excitation andmonitoring emission wavelength at 665 nm. Within the linear range of theassay, the observed signal at 665 nm was directly related tophosphorylated product and can be used to calculate the IC₅₀ values.

For the purpose of the Tables and Examples below, the Btk IC₅₀ of eachcompound is expressed as follows: A=a compound with IC₅₀ less than 0.1μM, B=a compound with IC₅₀ within the range of 0.1 μM to 1 μM, and C=acompound with a Btk IC₅₀ within the range of 1 μM to 10 M.

Analytical Methods

Analytical data was included within the procedures below, in theillustrations of the general procedures, or in the tables of examples.Unless otherwise stated, all ¹H NMR data were collected on a Varian 400MHz Mercury Plus, Inova, or 400-MR instrument and chemical shifts arequoted in parts per million (ppm). LC/MS and HPLC data are referenced tothe table of LC/MS and HPLC conditions using the lower case methodletter provided in Table 1.

TABLE 1 LC/MS and HPLC methods Method Conditions a LC/MS: The gradientwas 5-60% B in 1.5 min then 60-95% B to 2.5 min with a hold at 95% B for1.2 min (1.3 mL/min flow rate). Mobile phase A was 10 mM NH₄OAc, mobilephase B was HPLC grade MeCN. The column used for the chromatography is a4.6 × 50 mm MAC-MOD Halo C18 column (2.7 μm particles). Detectionmethods are diode array (DAD) and evaporative light scattering (ELSD)detection as well as positive/negative electrospray ionization. b LC/MS:The gradient was 30-60% B in 1.50 min then 60-95% B to 2.5 min with ahold at 95% B for 1.2 min (1.3 mL/min flow rate). Mobile phase A was 10mM NH₄OAc, mobile phase B was HPLC grade MeCN. The column used for thechromatography was a 4.6 × 50 mm MAC-MOD Halo C8 column (2.7 μmparticles). Detection methods were diode array (DAD) and evaporativelight scattering (ELSD) detection as well as positive/negativeelectrospray ionization. c LC/MS: The gradient was 5% B for 0.1 min,5-100% B in 5.1 min with a hold at 100% B for 0.5 min then 100-5% B in0.3 min (2.0 mL/min flow rate). Mobile phase A was 0.1% TFA in water,mobile phase B was HPLC grade MeCN. The column used for thechromatography was a 2.1 × 50 mm Phenomenex Luna Combi-HTS C8(2) column(5 μm particles) at a temperature of 55° C. Detection methods are diodearray (DAD) and evaporative light scattering (ELSD) detection underpositive APCI ionization conditions. d LC/MS: The gradient was 1-90% Bin 3.4 min, 90-100% B in 0.45 min, 100-1% B in 0.01 min, and then heldat 1% B for 0.65 min (0.8 mL/min flow rate). Mobile phase A was 0.0375%TFA in water, mobile phase B was 0.018% TFA in MeCN. The column used forthe chromatography was a 2.1 × 50 mm Venusil XBP-C18 column (5 μmparticles). Detection methods are diode array (DAD) and evaporativelight scattering (ELSD) detection as well as positive/negativeelectrospray ionization. e LC/MS: The gradient was 10% B for 0.1 min,10-100% B in 1.0 min with a hold at 100% B for 0.2 min then 100-10% B in0.1 min (1.0 mL/min flow rate). Mobile phase A was 0.1% TFA in water,mobile phase B was HPLC grade MeOH. The column used for thechromatography was a 2.1 × 30 mm Waters BEH C8 column (1.7 μm particles)at a temperature of 55° C. Detection methods are diode array (DAD) andevaporative light scattering (ELSD) detection under positive APCIionization conditions. f LC/MS: The gradient was 5% B for 0.1 min,5-100% B in 2.5 min with a hold at 100% B for 0.3 min then 100-5% B in0.1 min (2.0 mL/min flow rate). Mobile phase A was 0.1% TFA in water,mobile phase B was HPLC grade MeCN. The column used for thechromatography was a 2.1 mm × 50 mm Phenomenex Luna Combi-HTS C8(2)column (5 μm particles) at a temperature of 55° C. Detection methods arediode array (DAD) and evaporative light scattering (ELSD) detectionunder positive APCI ionization conditions. g LC/MS: The gradient was 5%B for 0.1 min, 5-100% B in 2.5 min with a hold at 100% B for 0.3 minthen 100-5% B in 0.1 min (2.0 mL/min flow rate). Mobile phase A was 0.1%TFA in water, mobile phase B was HPLC grade MeCN. The column used forthe chromatography was a 2.1 × 50 mm Phenomenex Luna Combi-HTS C8(2)column (5 μm particles) at a temperature of 65° C. Detection methods arediode array (DAD) and evaporative light scattering (ELSD) detectionunder positive APCI ionization conditions. h LC/MS: The gradient was10-100% MeCN (A) and 10 mM ammonium acetate in water (B) was used, at aflow rate of 1.0 mL/min (0-0.1 min 10% A, 0.1-1.1 min 10-100% A, 1.1-1.3min 100% A, 1.3-1.4 min 100-10% A). The column used for thechromatography was a 2.1 × 30 mm Waters BEH C8 column (1.7 μm particles)at a temperature of 55° C. Detection methods are diode array (DAD) andevaporative light scattering (ELSD) detection under positive APCIionization conditions. i HPLC: The gradient was 5-95% B over about 10min (25 mL/min flow rate). Mobile phase A was 0.1% TFA in water, mobilephase B was HPLC grade MeCN. The column used for the chromatography wasa 250 × 21.2 mm Phenomenex Luna C18(2) 100 Å AXIA column (10 μmparticles). Detection method is UV at wavelengths of 220 nM and 254 nM.j LC/MS: The gradient was 5-100% B in 3.4 min with a hold at 100% B for0.45 min, 100-5% B in 0.01 min, and then held at 5% B for 0.65 min (0.8mL/min flow rate). Mobile phase A was 10 mM NH₄HCO₃, mobile phase B wasHPLC grade MeCN. The column used for the chromatography is a 2.1 × 50 mmXbridge Shield RPC18 column (5 μm particles). Detection methods arediode array (DAD) and evaporative light scattering (ELSD) detection aswell as positive/negative electrospray ionization. k LC/MS: The gradientwas 0-60% B in 2.1 min then 60-100% B to 2.5 min, finally changed to 0%B in 0.02 min under this condition for 0.5 min (1 mL/min flow rate).Mobile phase A was H₂O containing 0.0375% TFA, mobile phase B was MeCNcontaining 0.018% TFA. The column used for the chromatography is a 2.1 ×30 mm Halo C18 column (2.7 μm particles). Detection methods are diodearray (DAD) and evaporative light scattering (ELSD) detection as well aspositive/negative electrospray ionization.) l LC/MS: The gradient was10-90% B in 1.15 min with a hold at 90% B for 0.4 min, 90-10% B in 0.01min and then held at 10% B for 0.54 min (1 mL/min flow rate). Mobilephase A 0.0375% TFA in water, mobile phase B was 0.018% TFA in MeCN. Thecolumn used for the chromatography is a 2.1 × 30 mm Halo C18 column (2.7μm particles). Detection methods are diode array (DAD) andpositive/negative electrospray ionization. m LC/MS: The gradient was10-80% B in 2.0 min then 80-80% B in 0.48 min, finally changed to 10% Bin 0.02 min under this condition for 0.5 min (1.0 mL/min flow rate).Mobile phase A was H₂O containing 0.0375% TFA, mobile phase B was MeCNcontaining 0.018% TFA. The column used for the chromatography is a 2.1 ×30 mm Halo C18 column (2.7 μm particles). Detection methods are diodearray (DAD) and positive/negative electrospray ionization. n HPLC: Thegradient was 0-30% B over 25 min (80 mL/min flow rate). Mobile phase Awas 0.09% TFA in water, mobile phase B was MeCN. The column used for thechromatography was a 50 × 250 mm Luna(2) C18 column (10 μm particles).Detection method is UV. o LC/MS: The gradient was 10-100% B in 3.4 minwith a hold at 100% B for 0.45 min, 100-10% B in 0.01 min, and then heldat 10% B for 0.65 min (0.8 mL/min flow rate). Mobile phase A was 0.0375%TFA in water, mobile phase B was 0.018% TFA in MeCN. The column used forthe chromatography was a 2.1 × 50 mm Venusil XBP-C18 column (5 μmparticles). Detection methods are diode array (DAD) and evaporativelight scattering (ELSD) detection as well as positive/negativeelectrospray ionization. p LC/MS: The gradient was 5-100% B in 3.4 minwith a hold at 100% B for 0.45 min, 100-5% B in 0.01 min, and then heldat 5% B for 0.65 min (0.8 mL/min flow rate). Mobile phase A was 10 mMNH₄HCO₃, mobile phase B was HPLC grade MeCN. The column used for thechromatography was a 2.1 × 50 mm Xbridge Shield RPC18 column (5 μmparticles). Detection methods are diode array (DAD) and evaporativelight scattering (ELSD) detection as well as positive/negativeelectrospray ionization. q HPLC: The gradient was a hold at 21% B for 1min and then 21-51% B over 7 min with a hold at 51% for 4 min (25.0mL/min flow rate). Mobile phase A was 0.075% TFA in water, mobile phaseB was 0.075% TFA in MeCN. The column used for the chromatography was a30 × 100 mm Luna C18 column (5 μm particles). Detection method is UV atwavelengths of 220 nm and 254 nm. r HPLC: The gradient was a hold at 25%B for 2 min and then 25-55% B over 12 min (25.0 mL/min flow rate).Mobile phase A was 0.075% TFA in water, mobile phase B was 0.075% TFA inMeCN. The column used for the chromatography was a 30 × 100 mm Luna C18column (5 μm particles). Detection method is UV at wavelengths of 220 nmand 254 nm. s HPLC: The gradient was 10-38% B over 20 min (80 mL/minflow rate). Mobile phase A was 0.09% TFA in water, mobile phase B wasMeCN. The column used for the chromatography was a 50 × 250 mm Luna(2)C18 column (10 μm particles). Detection method is UV. t HPLC: Thegradient was a hold at 5% B for 1 min and then 5-35% B over 12 min (25.0mL/min flow rate). Mobile phase A was 0.075% TFA in water, mobile phaseB was MeCN. The column used for the chromatography was a 30 × 100 mmLuna C18 column (5 μm particles). Detection method is UV at wavelengthsof 220 nm and 254 nm. u HPLC: The gradient was 7-37% B over 8 min with ahold at 37% B for 2 min (25.0 mL/min flow rate). Mobile phase A was0.04% NH₃•H₂O in water, mobile phase B was MeCN. The column used for thechromatography was a 25 × 150 mm Waters Xbridge column (5 μm particles).Detection method is UV at wavelengths of 220 nm and 254 nm. v LC/MS: Thegradient was 0-80% B in 3.4 min, 80-100% B in 0.45 min, 100-0% B in 0.01min, and then held at 0% B for 0.65 min (0.8 mL/min flow rate). Mobilephase A was 0.0375% TFA in water, mobile phase B was 0.018% TFA in MeCN.The column used for the chromatography was a 2.1 × 50 mm Venusil XBP-C18column (5 μm particles). Detection methods are diode array (DAD) andevaporative light scattering (ELSD) detection as well aspositive/negative electrospray ionization. w HPLC: The gradient was ahold at 18% B for 1 min and then 18-48% B over 12 min (25.0 mL/min flowrate). Mobile phase A was 0.075% TFA in water, mobile phase B was MeCN.The column used for the chromatography was a 30 × 100 mm Luna C18 column(5 μm particles). Detection method is UV at wavelengths of 220 nm and254 nm. x HPLC: The gradient was a hold at 23% B for 1 min and then23-53% B over 12 min (25.0 mL/min flow rate). Mobile phase A was 0.075%TFA in water, mobile phase B was MeCN. The column used for thechromatography was a 30 × 100 mm Luna C18 column (5 μm particles).Detection method is UV at wavelengths of 220 nm and 254 nm. y HPLC: Thegradient was a hold at 20% B for 1 min and then 20-35% B over 12 min(25.0 mL/min flow rate). Mobile phase A was 0.075% TFA in water, mobilephase B was MeCN. The column used for the chromatography was a 30 × 100mm Luna C18 column (5 μm particles). Detection method is UV atwavelengths of 220 nm and 254 nm. z HPLC: The gradient was a hold at 15%B for 1 min and then 15-45% B over 12 min (25.0 mL/min flow rate).Mobile phase A was 0.075% TFA in water, mobile phase B was MeCN. Thecolumn used for the chromatography was a 30 × 100 mm Luna C18 column (5μm particles). Detection method is UV at wavelengths of 220 nm and 254nm. aa HPLC: The gradient was a hold at 5% B for 0.2 min, 5-95% B over1.7 min with a hold at 95% B for 1.3 min (2.5 mL/min flow rate). Mobilephase A was 0.01% TFA in water, mobile phase B was 0.01% TFA in MeCN.The column used for the chromatography was a 4.6 × 50 mm SunFire C18column (3.5 μm particles) at a temperature of 50° C. Detection method isUV. ab HPLC: The gradient was a hold at 5% B for 0.2 min, 5-95% B over1.7 min with a hold at 95% B for 1.4 min (2.1 mL/min flow rate). Mobilephase A was 0.01% TFA in water, mobile phase B was 0.01% TFA in MeCN.The column used for the chromatography was a 4.6 × 50 mm XBridge C18column (3.5 μm particles) at a temperature of 50° C. Detection method isUV. ac HPLC: The gradient was a hold at 5% B for 0.2 min, 5-95% B over1.7 min with a hold at 95% B for 1.4 min (2.1 mL/min flow rate). Mobilephase A was 10 mM NH₄HCO₃, mobile phase B was MeCN. The column used forthe chromatography was a 4.6 × 50 mm XBridge C18 column (3.5 μmparticles) at 50° C. Detection method is UV. ad HPLC: The gradient was37-67% B over 23 min (80 mL/min flow rate). Mobile phase A was 0.04%NH₃•H₂O in water, mobile phase B was MeCN. The column used for thechromatography was a 50 × 300 mm Gemini column (10 μm particles).Detection method is UV at wavelengths of 220 nm and 254 nm. ae LC/MS:The gradient was 10% B for 0.1 min, 10-100% B in 1.0 min with a hold at100% B for 0.2 min then 100-10% B in 0.1 min (1.0 mL/min flow rate).Mobile phase A was 0.1% TFA in water, mobile phase B was HPLC gradeMeCN. The column used for the chromatography was a 2.1 × 30 mm WatersBEH C8 column (1.7 μm particles) at a temperature of 55° C. Detectionmethods are diode array (DAD) and evaporative light scattering (ELSD)detection under positive APCI ionization conditions. af HPLC: Thegradient was a hold at 10% B for 0.5 min, 20-100% B over 6.5 min, 95% Bfor 3 min, and then 95-10% B over 2 min (50.0 mL/min flow rate). Mobilephase A was 0.1% TFA in water and mobile phase B was HPLC grade MeCN.The column used for the chromatography was a 30 × 75 mm Phenomenex LunaC8(2) 100 Å AXIA column (5 μm particle). Detection methods were Waters996 diode-array detector and Alltech Varex III evaporativelight-scattering detector. ag HPLC: The gradient was a hold at 10% B for0.5 min, 40-75% B over 6.5 min, 95% B for 3 min, and then 95-10% B over2 min (50.0 mL/min flow rate). Mobile phase A was 0.1% TFA in water andmobile phase B was HPLC grade MeCN. The column used for thechromatography was a 30 × 75 mm Phenomenex Luna C8(2) 100 Å AXIA column(5 μm particle). Detection methods were Waters 996 diode-array detectorand Alltech Varex III evaporative light-scattering detector. ahInstrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 15mL TFA in 20 L H₂O; B: MeCN Column: Luna 100 × 30.0 mm, 5μ; Flow rate:25 mL/min; Monitor wavelength: 220 & 254 nm Gradient: an initial hold at21% B for 1 min, a gradient of 21% to 51% B in 12 min ai Instrument:Shimadzu LC-20AP preparative HPLC Column: Synergi Max-RP C18 250 × 80 mmi.d. 10 u Mobile phase: A for H₂O(0.09% TFA) and B for CH₃CN Gradient: Bfrom 15% to 43% in 25 min Flow rate: 40 mL/min Injection amount: 50 mgper injection aj Instrument: Gilson 281 semi-preparative HPLC systemMobile phase: A: TFA/H₂O = 0.075% v/v; B: MECN Column: Luna C18 100 ×30.0 mm, 5μ Flow rate: 25 mL/min Monitor wavelength: 220 & 254 nmGradient: Time B%  0.00  10 12.0  40 14.0  40 14.2 100 16.2 100 16.4  1018.0  10 ak Instrument: Gilson 281 semi-preparative HPLC system Mobilephase: A: TFA/H₂O = 0.075% v/v; B: MeCN Column: Luna C18 200 × 21.2 mm,5μ Flow rate: 25 mL/min Monitor wavelength: 220 & 254 nm Gradient: TimeB%  0.00  1 12.0  8 14.0  8 14.2 100 16.2 100 16.4  1 18.0  1 alInstrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 15mL TFA in 20 L H₂O; B: MeCN Column: Luna 100 × 30.0 mm, 5μ Flow rate: 25mL/min Monitor wavelength: 220 & 254 nm Gradient: an initial hold at 8%B for 1 min, a gradient of 8% to 38% B in 12 min am Instrument: Gilson281 semi-preparative HPLC system Mobile phase: A: TFA/H₂O = 0.075% v/v;B: MeCN Column: Luna C18 100 × 30.0 mm, 5μ Flow rate: 25 mL/min Monitorwavelength: 220 & 254 nm Gradient: Time B%  0.00  18  8.00  48 12.0  4812.1 100 13.6 100 13.7  18 14.7  18 an Instrument: Gilson 281semi-preparative HPLC system Mobile phase: A: 8 mL NH₃•H₂O in 20 L H₂O;B: MeCN Column: waters Xbridge 130 × 21.2 mm, 5μ Flow rate: 25 mL/minMonitor wavelength: 220 & 254 nm Gradient: an initial hold at 27% B for1 min, a gradient of 27% to 57% B in 12 min ao Instrument: ShimadzuLC-8A preparative HPLC Column: Luna(2) C18 250 × 50 mm i.d. 10 u Mobilephase: A for H₂O (0.09% TFA) and B for CH₃CN Gradient: B from 82% to 82%Flow rate: 100 mL/min Injection amount: 0.7 g per injection ap HPLC: Thegradient was a hold at 10% B for 0.5 min, 10-50% B over 6.5 min, 50-80%over 5 min, 80-100% over 0.5 min, with a hold at 100% B for 0.5 min (40mL/min flow rate). Mobile phase A was 0.01% TFA in water, mobile phase Bwas MeCN. The column used for the chromatography was a 30 × 75 mmSunFire C8 column (5 μm particles) at ambient temperature. Detectionmethod is UV. aq HPLC: The gradient was a hold at 10% B for 0.5 min,10-50% B over 3.5 min, 50-80% over 4 min, 80-100% over 1.0 min, with ahold at 100% B for 2.0 min (40 mL/min flow rate). Mobile phase A was0.01% TFA in water, mobile phase B was MeCN. The column used for thechromatography was a 30 × 75 mm SunFire C8 column (5 μm particles) atambient temperature. Detection method is UV. ar LC/MS: The gradient wasa hold at 5% B for 0.2 min, 5-95% B over 1.7 min with a hold at 95% Bfor 1.3 min (2.3 mL/min flow rate). Mobile phase A was 0.01% TFA inwater, mobile phase B was 0.01% TFA in MeCN. The column used for thechromatography was a 4.6 × 50 mm XBridge C18 column (3.5 μm particles)at a temperature of 50° C. Detection methods are diode array (DAD) underpositive APCI ionization conditions. as LC/MS: The gradient was 5-60% Bin 1.50 min then 60-95% B to 2.5 min with a hold at 95% B for 1.2 min(1.3 mL/min flow rate). Mobile phase A was 10 mM NH₄OAc, mobile phase Bwas HPLC grade MeCN. The column used for the chromatography was a 4.6 ×50 mm MAC-MOD Halo C8 column (2.7 μm particles). Detection methods werediode array (DAD) and evaporative light scattering (ELSD) detection aswell as positive/negative electrospray ionization. at LC/MS: Thegradient was 5-95% B over 1.2 min, with a hold at 95% for 1.3 min, backto 5% over 0.01 min (2.0 mL/min flow rate). Mobile phase A was 0.01% TFAin water, mobile phase B was 0.01% TFA in MeCN. The column used for thechromatography was a 4.6 × 50 mm SunFire C18 column (3.5 μm particles)at 50 C. Detection method is UV au LC/MS: The gradient was 5-95% B over1.3 min, with a hold at 95% for 1.5 min, back to 5% over 0.01 min (1.8mL/min flow rate). Mobile phase A was 0.01% ammonium acetate in water,mobile phase B was MeCN. The column used for the chromatography was a4.6 × 50 mm Xbridge C18 column (3.5 μm particles) at 50 C. Detectionmethod is UV av LC/MS: The gradient was 5-100% B over 1.2 min, with ahold at 100% for 1.3 min (2.0 mL/min flow rate). Mobile phase A was0.01% TFA in water, mobile phase B was 0.01% TFA in MeCN. The columnused for the chromatography was a 4.6 × 50 mm Sunfire C18 column (3.5 μmparticles) at 50 C. Detection method is UV and MS aw LC/MS: The gradientwas 5-95 % B over 1.3 min, with a hold at 95% for 1.5 min (1.8 mL/minflow rate). Mobile phase A was 0.01% ammonium acetate in water, mobilephase B was MeCN. The column used for the chromatography was a 4.6 × 50mm Xbridge C18 column (3.5 μm particles) at 50 C. Detection method is UVand MS ax LC/MS: The gradient was 5-100% B over 1.3 min (2.0 mL/min flowrate). Mobile phase A was 0.01% TFA in water, mobile phase B was 0.01%TFA in MeCN. The column used for the chromatography was a 4.6 × 50 mmSunfire C18 column (3.5 μm particles) at 45 C. Detection method is UVand MS ay LC/MS: The gradient was 5-100% B over 1.2 min, with a hold at95% for 1.3 min (2.0 mL/min flow rate). Mobile phase A was 0.01% TFA inwater, mobile phase B was 0.01% TFA in MeCN. The column used for thechromatography was a 4.6 × 50 mm Sunfire C18 column (3.5 μm particles)at 50 C. Detection method is UV and MS az LC/MS: The gradient was 5-100%B over 1.2 min, with a hold at 100% for 1.3 min (2.0 mL/min flow rate),then down to 95% over 0.01 min. Mobile phase A was 0.01% TFA in water,mobile phase B was 0.01% TFA in MeCN. The column used for thechromatography was a 4.6 × 50 mm Sunfire C18 column (3.5 μm particles)at 50 C. Detection method is UV and MS ba LC/MS: The gradient was 5-60%B in 1.50 min then 60-95% B to 2.5 min with a hold at 95% B for 1.2 min(1.3 mL/min flow rate). Mobile phase A was 0.1% formic acid in water,mobile phase B was HPLC grade MeCN. The column used for thechromatography was a 4.6 × 50 mm MAC-MOD Halo C18 column (2.7 μmparticles). Detection methods were diode array (DAD) and evaporativelight scattering (ELSD) detection as well as positive/negativeelectrospray ionization. bb LC/MS: The gradient was 5-60% B in 0.60 minthen 60-95% B to 1.00 min with a hold at 95% B for 0.30 min (1.3 mL/minflow rate). Mobile phase A was 10 mM ammonium acetate, mobile phase Bwas HPLC grade MeCN. The column used for the chromatography was a 2.1 ×50 mm ACE Excel 2 UHPLC C18 column (2.0 μm particles). Detection methodswere diode array (DAD) and evaporative light scattering (ELSD) detectionas well as positive/negative electrospray ionization. bc InstrumentGilson 281(PHG008) Column: waters X-bridge ODS C 18 19 × 250 mm, 10 μmMobile Phase: A: water (l0 ppM NH₄HC0₃); B: ACN Flow Rate: 30 mL/minMonitor wavelength: 220 & 254 nm Gradient: 10-60% B in 8 min, stop at 15min bd HPLC: The column used for the chromatography was a 21.2 × 250 mmHypersil C18 HS column (8 mm particles). The gradient was 40% B for 4min, 40-65 % B over 30 min (21 mL/min flow rate). Mobile phase A was0.05N aqueous NH₄OAc buffer (pH 4.5) and mobile phase B was HPLC gradeMeCN. Detection method is UV, 1 = 254 nm be LC/MS: The gradient was5-100% B over 1.2 min, with a hold at 100% for 1.3 min, then back downto 5% over 0.01 min (2.0 mL/min flow rate). Mobile phase A was 0.01% TFAin water, mobile phase B was 0.01% TFA in MeCN. The column used for thechromatography was a 4.6 × 50 mm Sunfire C18 column (3.5 μm particles)at 50 C. Detection method is UV and MS

TABLE 2 Chiral HPLC methods Method Conditions 1 The gradient was 20% Bin 15.25 min then 20-65% B in 0.05 min and held at 65% B for 6.70 min.Then equilibrated back down to 20% and held for 4 min. (20 mL/min flowrate). Mobile phase B was 1:1 EtOH/MeOH and mobile phase A was HPLCgrade heptane with 0.12% diethylamine added. The column used for thechromatography was a Daicel IA, 20 × 250 mm column (5 μm particles).Detection method was UV (λ = 264 nm) 2 The method was isocratic 25% Bfor 25 min (20 mL/min flow rate). Mobile phase B was EtOH and Mobilephase A was HPLC grade heptane with no modifier added. The column usedfor the chromatography was a Daicel IA, 20 × 250 mm column (5 μmparticles). Detection methods were evaporative light scattering (ELSD)detection and UV (λ = 312 nm) 3 (LC) The gradient was 40-65% B in 14.75min then step to 98% B and hold for 5.2 min (20 mL/min flow rate).Mobile phase B was EtOH (200 proof), mobile phase A was HPLC gradeheptane with 0.2% diethylamine added. The column used for thechromatography was a WhelkO1 R,R 21 × 250 mm column from RegisTechnologies (5 μm particles). 4 (SFC) Isocratic, 50% co-solvent B (80mL/min, 100 bar system pressure, 40° C.). Co-solvent B was 1:1 HPLCgrade EtOh:MeCN with 0.1% triethylamine added. Solvent A was SFC gradeCO₂. The column used for the chromatography was a 30 × 250 mm DaicelChiralpak AS-H (5 μm particles). 5 (LC) Isocratic 18% B for 20 min then18-30% B in 7 min and hold at 30% B for 6 min (20 mL/min flow rate).Mobile phase B was EtOH (200 proof), mobile phase A was HPLC gradeheptane with 0.2% diethylamine added. The column used for thechromatography was a WhelkO1 R,R 21 × 250 mm column from RegisTechnologies (5 μm particles). 6 (LC) Isocratic 9% B for 37.5 min thenstep to 40% B to elute second stereoisomer (20 mL/min flow rate). Mobilephase B was EtOH (200 proof), mobile phase A was HPLC grade heptane with0.2% diethylamine added. The chromatography used a Daicel IA, 21 × 250mm column (5 μm particles). 7 (LC) Isocratic 22% B for 19 min then stepto 35% B and hold for 3 min (20 mL/min flow rate). Mobile phase B wasEtOH (200 proof), mobile phase A was HPLC grade heptane with 0.2%diethylamine added. The chromatography used a Daicel IE, 20 × 250 mmcolumn (5 μm particles). 8 (LC) Isocratic 30% B for 15 min then 30-33% Bin 9 min then step to 45% B and hold for 4 min (20 mL/min flow rate).Mobile phase B was EtOH (200 proof), mobile phase A was HPLC gradeheptane with 0.2% diethylamine added. The chromatography used a DaicelIE, 20 × 250 mm column (5 μm particles). 9 (LC) Isocratic 15% B for 17min then step to 55% B and hold for 11 min (20 mL/min flow rate). Mobilephase B was EtOH (200 proof), mobile phase A was HPLC grade heptane with0.2% diethylamine added. The chromatography used a Daicel IC, 20 × 250mm column (5 μm particles). 10 (LC) Isocratic 20% B for 42 min (20mL/min flow rate). Mobile phase B was EtOH (200 proof), mobile phase Awas HPLC grade heptane with 0.2% diethylamine added. The chromatographyused a Daicel IC, 20 × 250 mm column (5 μm particles). 11 (LC) Isocratic25% B for 18.5 min then step to 60% B and hold for 4 min (20 mL/min flowrate). Mobile phase B was 200 proof EtOH, mobile phase A was HPLC gradeheptane with 0.2% diethylamine added. The column used for thechromatography was a WhelkO1 S,S 21 × 250 mm column from RegisTechnologies (5 μm particles). 12 LC) Isocratic 25% B for 15 min thenstep to 45% B and hold for 12 min (20 mL/min flow rate). Mobile phase Bwas HPLC grade IPA, mobile phase A was HPLC grade heptane with 0.2%diethylamine added. The column used for the chromatography was a DacielIC 20 × 250 mm column (5 μm particles). 13 LC) Isocratic 30% B for 15.5min then step to 35% B and hold for 20 min (20 mL/min flow rate). Mobilephase B was HPLC grade IPA, mobile phase A was HPLC grade heptane with0.2% diethylamine added. The column used for the chromatography was aDaciel IF 20 × 250 mm column (5 μm particles). 14 (LC) Isocratic 25% Bfor 25 min (20 mL/min flow rate). Mobile phase B was EtOH (200 proof),mobile phase A was HPLC grade heptane with 0.2% diethylamine added. Thechromatography used a Daicel IB, 20 × 250 mm column (5 μm particles). 15(LC) 40-45% B in 5 min, hold at 45% B for 23 min then step to 65% B andhold for 10 min (20 mL/min flow rate). Mobile phase B was EtOH (200proof), mobile phase A was HPLC grade heptane with no modifier added.The column used for the chromatography was a WhelkO1 S,S 21 × 250 mmcolumn from Regis Technologies (5μm particles). 16 (LC) Isocratic 19% Bfor 35 min (25 mL/min flow rate). Mobile phase B was HPLC grade MeCN,mobile phase A was HPLC grade water with no modifier added. Thechromatography used an Astec, Chirobiotic T 21.2 × 250 mm column (5 μmparticles). 17 (LC) Isocratic 25% B for 18.5 min then step to 50% B andhold for 5.5 min (20 mL/min flow rate). Mobile phase B was 200 proofEtOH, mobile phase A was HPLC grade heptane with 0.2% diethylamineadded. The column used for the chromatography was a Daicel IF, 20 × 250mm column (5 μm particles). 18 (LC) Isocratic 5% B for 37.5 min (20mL/min flow rate). Mobile phase B was 200 proof EtOH, mobile phase A wasHPLC grade heptane with 0.2% diethylamine added. The column used for thechromatography was a Daicel IB, 20 × 250 mm column (5 μm particles). 19(LC) Isocratic 20% B for 30 min (20 mL/min flow rate). Mobile phase Bwas 200 proof EtOH, mobile phase A was HPLC grade heptane with 0.2%diethylamine added. The column used for the chromatography was a DaicelIF, 20 × 250 mm column (5 μm particles).

General Purification Methods

For the general procedures, the final compounds may be purified by anytechnique or combination of techniques known to one skilled in the art.Some examples that are not limiting include column chromatography with asolid phase (i.e. silica gel, alumina, etc.) and a solvent (orcombination of solvents) that elutes the desired compounds (i.e.hexanes, heptane, EtOAc, DCM, MeOH, EtOH, MeCN, water, etc.);preparatory TLC with a solid phase (i.e. silica gel, alumina etc.) and asolvent (or combination of solvents) that elutes the desired compounds(i.e. hexanes, heptane, EtOAc, DCM, MeOH, EtOH, MeCN, water, etc.);reverse phase HPLC (see Table 1 for some non-limiting conditions);recrystalization from an appropriate solvent (i.e. MeOH, EtOH, IPA,EtOAc, toluene, etc.) or combination of solvents (i.e. EtOAc/heptane,EtOAc/MeOH, etc.); chiral LC with a solid phase and an appropriatesolvent (i.e. EtOH/heptane, MeOH/heptane, IPA/heptane, etc. with orwithout a modifier such as diethylamine, TFA, etc.) to elute the desiredcompound; chiral SFC with a solid phase and CO₂ with an appropriatemodifier (i.e. MeOH, EtOH, IPA with or without additional modifier suchas diethylamine, TFA, etc.); precipitation from a combination ofsolvents (i.e. DMF/water, DMSO/DCM, EtOAc/heptane, etc.); triturationwith an appropriate solvent (i.e. EtOAc, DCM, MeCN, MeOH, EtOH, IPA,n-PrOH, etc.); extractions by dissolving a compound in a liquid andwashing with an appropriately immiscible liquid (i.e. DCM/water,EtOAc/water, DCM/saturated NaHCO₃, EtOAc/saturated NaHCO₃, DCM/10%aqueous HCl, EtOAc/10% aqueous HCl, etc.); distillation (i.e. simple,fractional, Kugelrohr, etc.); gas chromatography using an appropriatetemperature, carrier gas and flow rate; sublimation at an appropriatetemperature and pressure; filtration through a media (i.e. Florosil®,alumina, Celite®, silica gel, etc.) with a solvent (i.e. heptane,hexanes, EtOAc, DCM, MeOH, etc.) or combination of solvents; saltformation with solid support (resin based, i.e. ion exchange) orwithout. Some descriptions of these techniques can be found in thefollowing references, Gordon, A. J. and Ford, R. A. “The Chemist'sCompanion”, 1972; Palleros, D. R. “Experimental Organic Chemistry”,2000; Still, W. C., Kahn, M. and Mitra, A. J. Org. Chem. 1978, 43, 2923;Yan, B. “Analysis and Purification Methods in Combinatorial Chemistry”2003; Harwood, L. M., Moody, C. J. and Percy, J. M. “ExperimentalOrganic Chemistry: Standard and Microscale, 2^(nd) Edition”, 1999;Stichlmair, J. G. and Fair, J. R. “Distillation; Principles andPractices” 1998; Beesley T. E. and Scott, R. P. W. “ChiralChromatography”, 1999; Landgrebe, J. A. “Theory and Practice in theOrganic Laboratory, 4^(th) Edition”, 1993; Skoog, D. A. and Leary, J. J.“Principles of Instrumental Analysis, 4^(th) Edition” 1992; Subramanian,G. “Chiral Separation Techniques 3^(rd) Edition” 2007; Kazakevich, Y.and Lobrutto, R. “HPLC for Pharmaceutical Scientists” 2007. Final orintermediate compounds prepared via any of the following GeneralProcedures can be optionally purified using one or more of thepurification methods described above.

PREPARATIONS AND EXAMPLES

The general synthetic methods used in each General Procedure follow andinclude an illustration of a compound that was synthesized using thedesignated General Procedure. None of the specific conditions andreagents noted herein are to be construed as limiting the scope of theinvention and are provided for illustrative purposes only. All startingmaterials are commercially available from Sigma-Aldrich (including Flukaand Discovery CPR) unless otherwise noted after the chemical name.Reagent/reactant names given are as named on the commercial bottle or asgenerated by IUPAC conventions, CambridgeSoft® ChemDraw Ultra 9.0.7,CambridgeSoft® Chemistry E-Notebook v9.0.127 or v11.0.3.68, or AutoNom2000. Compounds designated as salts (e.g. hydrochloride, acetate) maycontain more than one molar equivalent of the salt. Compounds of theinvention where the absolute stereochemistry has been determined by theuse of a commercially available enantiomerically pure starting materialor a stereochemically defined intermediate, or by X-ray diffraction aredenoted by an asterisk after the example number.

Preparation #1. 4-Bromo-2-iodo-1H-indole-7-carboxamide

Step A: 4-Bromo-1H-indole-7-carboxylic acid

To a solution of 4-bromo-2-nitrobenzoic acid (30 g, 122 mmol) inanhydrous THF (500 mL), a solution of vinylmagnesium bromide (51.2 mL,512 mmol, 1 N) in THF was added dropwise at about −30 to −50° C. Thereaction mixture was stirred at about −30 to −40° C. for about 2 h. Thenthe reaction mixture was poured into saturated aqueous NH₄Cl solutionand the mixture was extracted with EtOAc (200 mL×2). The combinedorganic layers were washed with brine, dried over andydrous Na₂SO₄,filtered and concentrated under reduced pressure to provide4-bromo-1H-indole-7-carboxylic acid (33 g crude), which was useddirectly for next step without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 11.42 (m, 1H), 8.11 (bs, 1H), 7.63 (dd, J=17.4, 8.0 Hz, 1H),7.45 (dt, J=14.2, 2.8 Hz, 1H), 7.32 (dd, J=21.9, 8.0 Hz, 1H), 6.47 (ddd,J=25.5, 3.1, 2.1 Hz, 1H).

Step B: Methyl 4-bromo-1H-indole-7-carboxylate

To a solution of 4-bromo-1H-indole-7-carboxylic acid (33 g, 137 mmol) inDMF (300 mL), Cs₂CO₃ (90 g, 276 mmol) was added and stirred at rt for 1h. Then iodomethane (29.3 g, 206 mmol) was added dropwise at about 0° C.The reaction mixture was warmed to rt for about 3 h. The mixture waspoured into water and extracted with EtOAc (200 mL×2). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure and the residue waspurified by silica gel column chromatography to provide methyl4-bromo-1H-indole-7-carboxylate (13.8 g, 20%): ¹H NMR (CDCl₃) δ 9.98 (s,1H), 7.76-7.74 (d, J=8, 1H), 7.39-7.34 (m, 2H), 6.68-6.66 (m, 1H), 4.00(s, 3H).

Step C: Methyl 4-bromo-1-tosyl-1H-indole-7-carboxylate

To a solution of methyl 4-bromo-1H-indole-7-carboxylate (130 g, 512mmol) in anhydrous THF (1500 mL) was added NaH (18.4 g, 767 mmol) inportions at about 0° C. and stirred for about 1 h at 0° C. Then TsCl(117 g, 614 mmol) was added in portions at about 0° C. The reactionmixture was warmed to rt for about 2 h. The reaction mixture was pouredinto ice water and extracted with EtOAc (1000 mL×2). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure and the residue waspurified by silica gel column chromatography to provide methyl4-bromo-1-tosyl-1H-indole-7-carboxylate (150 g, 72%): ¹H NMR (CDCl₃) δ7.60-7.58 (d, J=8.4, 2H), 7.54-7.53 (d, J=3.6, 1H), 7.46-7.44 (d, J=8,1H), 7.37-7.35 (d, J=8.4, 1H), 7.21-7.18 (d, J=8.4, 2H), 6.77-6.76 (m,1H), 3.93 (s, 3H), 2.35 (s, 3H).

Step D: Methyl 4-bromo-2-iodo-1-tosyl-1H-indole-7-carboxylate

To a solution of diisopropylamine (6.2 g, 61.2 mmol) in anhydrous THF(100 mL), stirred in t-BuLi (3.92 g, 61.2 mmol) in pentane was added atabout 0° C. under N₂ atmosphere, and the mixture was stirred for about10 min. The solution of methyl 4-bromo-1-tosyl-1H-indole-7-carboxylate(10 g, 24.49 mmol) in anhydrous THF (100 mL) was added at about −70° C.under N₂ atmosphere. After about 30 min, a solution of I₂ (9.33 g, 36.7mmol) in anhydrous THF (50 mL) was added. After about 30 min, thecooling bath was removed and the mixture was stirred for about anotherhour. The mixture was quenched with saturated aqueous Na₂S₂O₃. Water andEtOAc were added to the mixture. The layers were separated and theaqueous layer was extracted with EtOAc (300 mL×2). The combined organiclayers were washed with brine, dried with anhydrous Na₂SO₄, filtered,concentrated under reduced pressure and the residue was purified bysilica gel column chromatography to provide methyl4-bromo-2-iodo-1-tosyl-1H-indole-7-carboxylate (7.5 g, 38%): ¹H NMR(CDCl₃): δ 7.64-7.59 (m, 2H), 7.55-7.53 (m, 2H), 7.30-7.27 (m, 2H),7.17-7.17 (m, 1H), 4.06-4.05 (d, J=1.2, 3H), 2.49 (s, 3H).

Step E: 4-Bromo-2-iodo-1H-indole-7-carboxylic acid

To a solution of methyl 4-bromo-2-iodo-1-tosyl-1H-indole-7-carboxylate(75 g, 23.4 mmol) in MeOH (750 mL), THF (1500 mL) and water (750 mL),LiOH (67 g, 280 mmol) was added the the reaction mixture was heated atabout 45° C. for about 3 h. The resulting solution was concentratedunder reduced pressure to remove MeOH and THF, then the solution wasadjusted to pH=6 to 7 with HCl (1 N), the precipitate was filtered anddried by high vacuum to provide 4-bromo-2-iodo-1H-indole-7-carboxylicacid (45 g, 88%): ¹H NMR (DMSO-d6) δ 11.60 (s, 1H), 7.56 (d, J=8.0, 1H),7.31 (m, J=8.0, 1H), 6.72 (s, 1H).

Step F: 4-bromo-2-iodo-1H-indole-7-carboxamide

To a solution of 4-bromo-2-iodo-1H-indole-7-carboxylic acid (45 g, 123mmol) in DMF (450 mL) was added HOBt (28.2 g, 184 mmol), PyBOP (96 g,184 mmol), NH₄Cl (10 g, 184.5 mmol) and DIEA (63.6 g, 492 mmol). Thereaction mixture was stirred at rt for about 2 h. Water was added, thereaction mixture was extracted with EtOAc (1000 mL×2), the organic phasewas dried with anhydrous Na₂SO₄ and concentrated under reduced pressureand the residue was purified by column chromatography with Petether:EtOAc (20:1 to 1:1) to provide4-bromo-2-iodo-1H-indole-7-carboxamide (25 g, 56%): ¹H NMR (DMSO-d6) δ11.62 (s, 1H), 8.24 (s, 1H), 7.62-7.60 (d, J=8, 2H), 7.38-7.36 (d, J=8,1H), 6.77 (s, 1H): LC/MS (Table 1, Method d) 14=3.07 min; MS m/z: 366(M−H)⁻.

Preparation #2. 4-Bromo-1H-indole-7-carboxamide

To a solution of 4-bromo-1H-indole-7-carbonitrile (3 g, 13.57 mmol,Sinova) in EtOH (36.2 mL)/DMSO (9.05 mL) was slowly added added hydrogenperoxide (28.0 mL, 274 mmol) and NaOH (28.0 mL, 28.0 mmol). The reactionmixture was stirred at rt for about 1 h. Water was added and theprecipitate was collected by filtration, washed with water, and driedunder vacuum to provide 4-bromo-1H-indole-7-carboxamide (2.85 g, 88%).LC/MS (Table 1, Method f)₁4=1.42 min; MS m/z: 280 (M+MeCN)⁺.

Preparation #3.2-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one

Step A: 3,4-Dihydroisoquinolin-1(2H)-one

To a solution of 2,3-dihydro-1H-inden-1-one (30 g, 227 mmol) in DCM (300mL) was added methanesulfonic acid (300 mL) and the solution was cooledto about 0° C. Sodium azide (30 g, 461 mmol) was added to the solutionin portions at about 0° C. and the reaction mixture was stirredovernight at rt. The reaction mixture was neutralized with 20% aqueousNaOH and extracted with DCM (2×1 L). The organic phase was dried withanhydrous Na₂SO₄ and concentrated to give a residue, which was purifiedby column chromatography on silica gel to provide3,4-dihydroisoquinolin-1(2H)-one (5 g, 15%): ¹H NMR (MeOD) δ 7.93-7.91(m, 1H), 7.49-7.45 (m, 1H), 7.36-7.45 (m, 1H), 7.28-7.26 (d, 1H),3.50-3.46 (t, 2H), 2.97-2.94 (t, 2H).

Step B: 2-(3-Bromo-2-methylphenyl)-3,4-dihydroisoquinolin-1(2H)-one

A mixture of 3,4-dihydroisoquinolin-1(2H)-one (3.5 g, 13.6 mmol),1,3-dibromo-2-methylbenzene (17.5 g, 70.5 mmol) and K₂CO₃ (9.85 g, 71.3mmol) in DMSO (40 mL) was purged with N₂, treated with CuI (1.75 g, 9mmol) and heated to about 160° C. for about 4 h. The reaction mixturewas diluted with DCM and filtered through Celite®. The filtrate waswashed with 5% ammonia hydroxide, dried and concentrated. The residuewas purified by column chromatography on silica gel to provide2-(3-bromo-2-methylphenyl)-3,4-dihydroisoquinolin-1(2H)-one (6 g, 80%):¹H NMR (CDCl₃) δ8.16-8.14 (d, 1H), 7.56-7.54 (d, 2H), 7.49-7.41 (t, 1H),7.26 (d, 1H), 7.25-7.18 (d, 1H), 7.15-7.13 (d, 1H), 3.98-3.92 (m, 1H),3.76-3.70 (m, 1H), 3.30-3.22 (m, 1H), 3.13-3.07 (m, 1H) 2.36 (s, 3H).

Step C:2-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one

To a mixture of2-(3-bromo-2-methylphenyl)-3,4-dihydroisoquinolin-1(2H)-one (4.6 g, 14.6mmol), bis(pinacolato)diboron (8.8 g, 34.6 mmol) and CH₃COOK (9 g, 91.8mmol) in 1, 4-dioxane (100 mL) and DMSO (20 mL), PdCl₂ (dppf) (1 g, 1.4mmol) was added. The reaction mixture was heated at about 120° C.overnight under N₂ protection. After cooling to ambient temperature, thereaction mixture was filtered through Celite® the solid was washed withEtOAc, and the filtrate was washed with water and brine, dried overNa₂SO₄, concentrated and the residue was purified by columnchromatography on silica gel to provide2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4-dihydroisoquinolin-1(2H)-one(1.5 g, 28%): ¹H NMR (CDCl₃) δ 8.19-8.17 (dd, 1H), 7.80-7.78 (dd, 1H),7.51-7.47 (t, 1H), 7.42-7.38 (t, 1H), 7.32-7.25 (m, 3H), 3.96-3.89 (m,1H), 3.77-3.71 (m, 1H), 3.27-3.23 m, 1H), 3.14-3.08 (m, 1H), 2.50 (s,3H), 1.36 (s, 12H); LC/MS (Table 1, Method o) R_(t)=3.34 min; MS m/z:364 (M+H)⁺.

Preparation #4.N-(2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazole-2-carboxamide

To a solution of2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.9 g,8.15 mmol, CombiBlocks) in DCM (50 mL), DIEA (2.1 g, 16.3 mmol) and HATU(4.03 g, 10.6 mmol) were added at rt. After about 5 min,thiazole-2-carboxylic acid (1.9 g, 8.15 mmol) was added and the solutionwas stirred for about 3 h at rt. The reaction mixture was poured intowater, extracted with DCM (100 mL×2) and the organic phase was washedwith brine, dried with anhydrous Na₂SO₄ and concentrated under reducedpressure and the residue was purified by column chromatography on silicagel (eluted with Pet ether:EtOAc=10:1 to 3:1) to provideN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazole-2-carboxamide(1 g, 36%): ¹H NMR (CDCl₃) δ 9.07 (s, 1H), 8.16-8.14 (d, J=8 Hz, 1H),7.87-7.86 (t, J=3.2 Hz, 1H), 7.57-7.55 (m, 2H), 7.20-7.18 (m, 1H), 2.53(s, 3H), 1.29 (s, 12H).

Preparation #5.1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

Step A: 5-Bromo-1-methylpyridin-2(H)-one

To a solution of 5-bromopyridin-2-ol (4 g, 23 mmol) in THF (200 mL) atabout 0° C. was added NaH (0.83 g, 34.7 mmol) in portions. The reactionmixture was stirred at rt for about 15 min followed by addition ofiodomethane (9.8 g, 69 mmol). The mixture was stirred overnight at rt.After the completion of the reaction (TLC monitoring), the reactionmixture was cooled to about 0° C., water was added, extracted with EtOAc(100 mL×2). The organic layer was washed with brine, dried withanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toprovide 5-bromo-1-methylpyridin-2-(1H)-one (3 g, 69%): ¹H NMR (MeOD) δ7.87 (s, 1H), 7.58-7.55 (m, 1H), 6.47 (d, J=9.6 Hz, 1H), 3.53 (s, 3H).

Step B:1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

To a mixture of 5-bromo-1-methylpyridin-2(1H)-one (1.0 g, 5.32 mmol),KOH (0.78 g, 7.98 mmol) and bis(pinacolato)diboron (0.162 g, 6.38 mmol)in 1,4-dioxane (20 mL), tricyclohexylphosphine (149 mg, 0.532 mmol),Pd₂dba₃ (487 mg, 0.532 mmol) were added under N₂ atmosphere. The mixturewas stirred at about 80° C. for about 5 h. Then water was added, theaqueous layer was extracted with EtOAc (50 mL×2), and the organic layerwas dried over anhydrous Na₂SO₄, concentrated under reduced pressure andthe residue was purified by column chromatograph on silica gel toprovide1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(H)-one(0.80 g, 64%): ¹H NMR (CDCl₃) δ 7.70 (s, 1H), 7.54 (d, J=8.8 Hz, 1H),6.47 (d, J=8.8 Hz, 1H), 3.49 (s, 3H), 1.24 (s, 12H).

Preparation #6.4-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)pyrimidine-2-carbonitrile

To a microwave vial was added 4-chloropyrimidine-2-carbonitrile (100 mg,0.717 mmol, CombiPhos),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (314 mg, 1.433mmol), and N-ethyl-N-isopropylpropan-2-amine (0.250 mL, 1.433 mmol) inMeCN (7 mL). The vial was sealed and heated in a microwave at about 150°C. for about 20 min with stirring. The reaction mixture was cooled to rtand the solvent removed under a warm stream of nitrogen. The residue wasdissolved in DCM (10 mL) and washed with water (10 mL). The mixture wasseparated using a Biotage phase separator and the organics wereconcentrated in vacuo to afford the crude product. The crude product wasadded to a silica gel column and was eluted with 10-60% EtAcO/heptane toprovide4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)pyrimidine-2-carbonitrile(0.11 g, 48%): LC/MS (Table 1, Method f) R_(t)=1.89 min; MS m/z: 323(M+H)⁺.

Preparation #7.N-(3-(3-amino-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide

Step A: 4-Bromo-1H-indole-7-carboxylic acid

To a solution of methyl 4-bromo-1H-indole-7-carboxylate (6 g, 23 mmol,Preparation #1 step B) in THF (300 mL), water (60 mL) and MeOH (60 mL)was added lithium hydroxide (2.83 g, 118 mmol). Then the mixture washeated to reflux overnight. After cooling to rt, the solvent was removedunder reduced pressure, the aqueous layer was acidified by addition of 4N HCl to about pH 6. The precipitate was filtered, and the solid wasdried to provide 4-bromo-1H-indole-7-carboxylic acid (5.5 g, 97%): ¹HNMR (DMSO-d6) δ 11.39 (br, 1H), 7.65-7.63 (d, J=8.0 Hz, 1H), 7.46-7.44(m, 1H), 7.33-7.31 (d, J=8.0 Hz, 1H), 6.49-6.48 (m, 1H).

Step B: 4-Bromo-1H-indole-7-carboxamide

A solution of 4-bromo-1H-indole-7-carboxylic acid (5.5 g, 22.91 mmol)EDC (6.59 g, 34.4 mmol) and HOBt (5.26 g, 34.4 mmol) in THF (150 mL) andDCM (180 mL) was stirred at rt for 1 h. The mixture was then bubbledwith NH₃ gas for about 15 min and the resulting mixture was stirred atrt overnight. The mixture was diluted by addition of water and extractedwith DCM. The organic phase was washed with brine, dried andconcentrated to give a residue, which was suspended in ether andfiltered to provide 4-bromo-1H-indole-7-carboxamide (5.3 g, 97%): ¹H NMR(DMSO-d6) δ 11.40 (br, 1H), 8.08 (br, 1H), 7.29-7.57 (d, J=7.6 Hz, 1H),7.43-7.42 (m, 2H), 7.28-7.26 (d, J=7.6 Hz, 1H), 6.43-6.42 (m, 1H).

Step C: 4-Bromo-3-nitro-1H-indole-7-carboxamide

To a solution of 4-bromo-1H-indole-7-carboxamide (5.3 g, 22.17 mmol) andAgNO₃ (11.30 g, 66.5 mmol) in CH₃CN (100 mL) was added benzoyl chloride(9.35 g, 66.5 mmol) in CH₃CN (20 mL) at about 0° C. and the mixture wasstirred at about 0° C. for 1 h in the dark. Water and EtOAc was added.The organic phase was concentrated to give a residue which was washedwith DCM to provide 4-bromo-3-nitro-1H-indole-7-carboxamide (2.6 g,41%): ¹H NMR (DMSO-d6) δ 12.46 (br, 1H), 8.39-8.38 (d, J=3.6 Hz, 1H),8.33 (br, 1H), 7.77-7.73 (m, 2H), 7.67-7.62 (m, 1H). LC/MS (Table 1,Method 1) R_(t)=2.41 min; MS m/z: 285 (M+H)⁺.

Step D:N-(3-(7-Carbamoyl-3-nitro-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide

To a solution of 4-bromo-3-nitro-1H-indole-7-carboxamide (4 g, 14 mmol),N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazole-2-carboxamide(5.8 g, 16.9 mmol, Preparation #4) in 1,4-dioxane (100 mL) and water (25mL) was added Pd(PPh₃)₄ (0.81 g, 0.7 mmol) and CsF (6.4 g, 42 mmol) andthe mixture was stirred at about 120° C. overnight under N₂. Aftercooling to rt, the mixture was diluted by addition of water andextracted with EtOAc. The organic phase was dried and concentrated underreduced pressure to give a residue, which was purified by prep-HPLC(Table 1, Method ah) to provide crudeN-(3-(7-carbamoyl-3-nitro-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide(2 g, 33%): LC/MS (Table 1, Method 1) R_(t)=1.44 min; MS m/z: 422(M+H)⁺.

Step E:N-(3-(3-Amino-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide

To a solution ofN-(3-(7-carbamoyl-3-nitro-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide(0.20 g, 0.48 mmol) in EtOH (20 mL) was added Raney Ni (0.10 g) and themixture was stirred at rt under H₂ 50 psi for about 6 h. The mixture wasfiltered and the filtrate was concentrated under reduced pressure toprovide crudeN-(3-(3-amino-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide(0.11 g, 59%) which was used without further purification: LC/MS (Table1, Method 1) R_(t)=1.54 min; MS m/z: 392 (M+H)⁺.

Preparation #8.4-Hydroxy-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)cyclohexanecarboxamide

Step A: Ethyl 4-hydroxy-4-(trifluoromethyl)cyclohexanecarboxylate

A round bottom flask was charged with ethyl 4-oxocyclohexanecarboxylate(10.0 g, 58.8 mmol) and CsF (8.92 g, 58.8 mmol) in DME (100 mL) at about23° C. The reaction was cooled in an ice bath to about 5° C., thentrimethyl(trifluoromethyl)silane (8.35 g, 58.8 mmol) was added dropwiseat such a rate as to maintain reaction temperature below 8° C. Thereaction was stirred about 18 h at about 23° C. TBAF (19.4 mL, 1Msolution in THF, 19.39 mmol) was added drop wise and the mixture wasstirred about 20 min. The mixture was diluted with EtOAc (200 mL) andwashed with water (3×200 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified on silica gel using a gradient 10 to 50% EtOAc in heptanetogive ethyl 4-hydroxy-4-(trifluoromethyl)cyclohexanecarboxylate (9.27 g,67%). The product was taken as a mixture of isomers to the next stepwithout further purification: ¹H NMR (DMSO-d6) δ 5.73 (s, 0.5H), 5.72(s, 0.5H), 4.13-4.01 (m, 2H), 2.70-2.64 (m, 0.55H), 2.37-2.27 (m,0.45H), 1.90-1.45 (m, 8H), 1.21-1.14 (m, 3H).

Step B: (1s,4s)-4-Hydroxy-4-(trifluoromethyl)cyclohexanecarboxylic acid

Dry EtOH (90 mL) was treated with sodium (1.03 g, 45.0 mmol) at rt andthe mixture was stirred until the sodium dissolved. A solution of ethyl4-hydroxy-4-(trifluoromethyl)cyclohexanecarboxylate (9.00 g, 37.5 mmol)in EtOH (90 mL) was added and the mixture was heated at about 70° C.under nitrogen for about 18 h. To the mixture was added 2N aqueous NaOH(18.7 mL, 37.5 mmol) and the mixture was stirred with heating at about70° C. for about 4 h. The reaction was cooled to rt and concentrated toremove most of the EtOH. The resulting suspension was diluted with water(50 mL) to give a clear solution. The solution was acidified with conc.HCl to pH=2. The solution was concentrated to a volume of about 50 mLand the precipitated product was collected by filtration. Theprecipitate was rinsed with water (2×8 mL) and dried for about 18 hunder reduced pressure to give(1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexanecarboxylic acid as awhite solid (5.99 g, 75%): LC/MS (Table 1, Method a) R_(t)=1.35 min; MSm/z 211 (M−H)⁻, ¹H NMR (DMSO-d6) δ 12.10 (s, 1H), 5.69 (s, 1H),2.26-2.16 (m, 1H), 1.79-1.69 (m, 4H), 1.69-1.56 (m, 2H), 1.55-1.44 (m,2H).

Step C:(1s,4s)-4-Hydroxy-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)cyclohexanecarboxamide

A solution containing(1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexanecarboxylic acid (100 mg,0.471 mmol) and2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (110 mg,0.471 mmol, CombiBlocks) in DMF (2.0 mL) was treated with DIEA (0.082mL, 0.471 mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (179 mg, 0.471 mmol) and the mixture was stirredat rt for about 1 h. The mixture was diluted with water (5 mL),triturated and the supernatant decanted. The residue was dissolved inEtOAc (10 mL), dried over Na₂SO₄, filtered and concentrated. The residuewas purified on silica gel using a gradient of 25-75% EtOAc in heptane.Product fractions were combined, concentrated and dried to solids underreduced pressure to give(1s,4s)-4-hydroxy-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(trifluoromethyl)cyclohexanecarboxamideas a solid (135 mg, 67%): LC/MS (Table 1, Method b) R_(t)=1.56 min; MSm/z 428 (M+H)⁺, ¹H NMR (DMSO-d6) δ 9.23 (s, 1H), 7.46 (dd, J=7.4, 1.4Hz, 1H), 7.35 (dd, J=7.9, 1.4 Hz, 1H), 7.14 (t, J=7.6 Hz, 1H), 5.74 (s,1H), 2.44-2.34 (m, 1H), 2.32 (s, 3H), 1.90-1.67 (m, 6H), 1.60-1.42 (m,2H), 1.30 (s, 12H).

Preparation #9: 4-Bromo-1H-pyrrolo[3,2-c]pyridine-7-carboxamide

Step A: 4-Bromo-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid

A solution of 6-bromo-4-nitronicotinic acid (3.8 g, 15.4 mmol, Eur. J.Med. Chem. 1977, 12(6), 541) in anhydrous THF (100 mL) was stirredbetween about −40 and −50° C. for about 5 min. Then vinylmagnesiumbromide (1N in THF, 69.2 mL, 69.2 mmol) was added dropwise. The mixturewas stirred between about −40 and −50° C. for about 4 h. The mixture wasquenched with saturated aqueous NH₄Cl (2 mL). The solvent was removedunder reduced pressure to get a residue, which was purified by prep-HPLC(Table 1, Method w) to provide4-bromo-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (1 g, 27%): ¹H NMR(DMSO-d6) δ 11.90 (br. s, 1H), 8.46 (s, 1H), 7.54 (t, J=2.65 Hz, 1H),6.56 (br, 1H).

Step B: 4-Bromo-1H-pyrrolo[3,2-c]pyridine-7-carboxamide

To a solution of 4-bromo-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid(100 mg, 0.42 mmol) in DMF (2 mL) was added HOBt (95 mg, 0.62 mmol) andEDCI (119 mg, 0.62 mmol). After the reaction mixture was stirred at rtfor about 1 h, NH₃/THF (10 mL) was added and the resulting mixture wasstirred at rt overnight. Then the suspension was filtered and thefiltrate was concentrated under reduced pressure. Water was added andextracted with EtOAc. The combined organic phase was washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure toprovide 4-bromo-1H-pyrrolo[3,2-c]pyridine-7-carboxamide (60 mg, 42%).The product was used without further purification: ¹H NMR (DMSO-d6) δ11.89 (br, 1H), 8.51 (s, 1H), 8.27 (br, 1H), 7.68 (br, 1H), 7.52-7.51(d, J=2.8 Hz, 1H), 6.52-6.51 (d, J=3.2 Hz, 1H).

Preparation #10.4-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide

Step A: Methyl4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate

To a solution of methyl 4-bromo-1H-indole-7-carboxylate (35 g, 138 mmol,Preparation #1 step B) in anhydrous THF (1500 mL) was added NaH (10 g,250 mmol) in portions at about 0° C. and stirred for 1 h at about 0° C.Then SEMCl (31.9 mL, 180 mmol) was added in portions at about 0° C. Thereaction mixture was allowed to warm up to rt and stirred for about 12h. Then to the reaction mixture was added saturated aqueous NH₄Cl andextracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give the residue, which was purified by columnchromatography on silica gel to give methyl4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate (32g, 60%): ¹H NMR (CDCl₃) δ 7.62-7.60 (d, J=8.4 Hz, 1H), 7.46-7.44 (d,J=8.0 Hz, 1H), 7.36-7.35 (d, J=3.2 Hz, 1H), 6.77-6.76 (d, J=3.6 Hz, 1H),5.80 (s, 2H), 4.06 (s, 3H), 3.32-3.28 (t, J=8.0 Hz, 2H), 0.89-0.85 (t,J=8.0 Hz, 2H), 0.00 (s, 9H).

Step B: Methyl4-bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate

To a solution of methyl4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate (10g, 26 mmol, Preparation #1 step B) in anhydrous THF (200 mL) was addedlithium diisopropylamide (18 mL, 36 mmol) at about −70° C. and stirredfor about 2 h. Then a solution of 12 (10 g, 39 mmol) in anhydrous THF(50 mL) was added to above solution dropwise at about −70° C. and thenstirred for about 2 h. The mixture was poured into aqueous Na₂S₂O₃solution and extracted with EtOAc. The combined organic phases werewashed with brine, dried over Na₂SO₄, filtered and concentrated underpressure to get a residue, which was purified by column chromatography(eluted with Pet ether:EtOAc=200:1) to provide methyl4-bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate(6.2 g, 47%): ¹H NMR (CDCl₃) δ 7.50-7.48 (d, J=8.0 Hz, 1H), 7.42-7.40(d, J=8.0 Hz, 1H), 7.10 (s, 1H), 5.90 (s, 2H), 4.06 (s, 3H), 3.29-3.25(t, J=8.0 Hz, 2H), 0.87-0.83 (t, J=8.0 Hz, 2H), 0.00 (s, 9H).

Step C: Methyl4-bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate

To a solution of methyl4-bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate(1.1 g, 2.2 mmol) in DME (20 mL) and water (5 mL) was added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.49 g, 2.37 mmol), PdCl₂(dppf) (0.176 g, 0.216 mmol) and Na₂CO₃ (0.894g, 6.47 mmol). The mixture was heated to reflux for about 3 h. Aftercooling to rt, water (20 mL) was added to the solution and extractedwith EtOAc (50 mL). The organic phase was dried over Na₂SO₄ andconcentrated in vacuo to get a crude product, which was purified bycolumn chromatography on silica gel (eluted with Pet ether:EtOAc=10:1)to provide methyl4-bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate(0.65 g, 65%): H NMR (CDCl₃) δ 7.84 (s, 1H), 7.77 (s, 1H), 7.61-7.59 (d,J=7.2 Hz, 1H), 7.49-7.40 (d, J=8.0 Hz, 1H), 6.79 (s 1H), 5.84 (s, 2H),4.14 (s, 3H), 4.11 (s, 3H), 3.20-3.16 (t, J=8.4 Hz, 2H), 0.82-0.78 (t,J=8.4 Hz, 2H), 0.00 (s, 9H).

Step D:4-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethysilyl)ethoxy)methyl)-1H-indole-7-carboxylicacid

To a solution of methyl4-bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate(0.65 mg, 1.41 mmol) in THF (10 mL), MeOH (2 mL) and water (2 mL) wasadded LiOH (0.17 mg, 7.04 mmol). The mixture was heated to reflux forabout 4 h. After cooling to rt, the solvent was removed under reducedpressure and the aqueous layer was acidified with aqueous HCl (1N) topH=4, extracted with EtOAc (10 mL), dried over Na₂SO₄, and concentratedunder reduced pressure to provide4-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylicacid (0.63 g, 99%): ¹H NMR (CDCl₃) δ 7.90 (s, 1H), 7.81 (s, 1H),7.80-7.79 (d, J=2.4 Hz, 1H), 7.54-7.52 (d, J=8.0 Hz, 1H), 6.84 (s, 1H),5.95 (s, 2H), 4.18 (s, 3H), 3.25-3.20 (t, J=7.2 Hz, 2H), 0.82-0.78 (t,J=7.2 Hz, 2H), 0.00 (s, 9H).

Step E:4-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide

To a solution of4-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylicacid (0.63 g, 1.4 mmol) in DMF (10 mL) was added PyBOP (1.46 g, 2.80mmol), HOBt (0.43 g, 2.80 mmol), NH₄Cl (0.11 g, 2.10 mmol) and DIEA(0.72 g, 5.60 mmol). The mixture was stirred at rt for about 2 h. Water(20 mL) was added to the mixture and extracted with EtOAc (30 mL). Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure to get a crude product, which was purified by columnchromatography on silica gel (eluted with Pet ether:EtOAc=3:1) toprovide crude4-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide.It was dissolved in in anhydrous THF (10 mL) was added (2.02 g, 12.2mmol) and ethane-1,2-diamine (2.20 g, 36.7 mmol) and heated to about100° C. for about 2 h. After cooling to rt, water was added to dilutethe mixture, extracted with EtOAc, the organic phase was dried overNa₂SO₄, and concentrated under reduced pressure to give a residue, whichwas purified by column chromatography on silica gel (eluted with Petether:EtOAc=3:1) to provide4-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide (0.20 g,51%): ¹H NMR (CDCl₃) δ 10.40 (br, 1H), 7.87 (s, 1H), 7.75 (s, 1H),7.30-7.28 (d, J=8, 1H), 7.20-7.18 (d, J=8, 1H), 6.64 (s, 1H), 6.05 (br,2H), 3.99 (s, 3H).

Preparation #11.3-(2-(((tert-Butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-fluoroquinazolin-4(3H)-one

Step A: (2-Amino-6-bromophenyl)methanol

The solution of 2-amino-6-bromobenzoic acid (19.8 g, 91.7 mmol) in THF(190 mL) was added to the suspension of LiAlH₄ (7.00 g, 183 mmol) in THF(190 mL) dropwise at about 0° C. After the addition was complete, themixture was stirred at rt for about 4 h. Then the mixture was quenchedwith EtOAc (180 mL). The mixture was poured into H₂O (1.1 L) andfiltered. The filtrate was extracted with EtOAc (3×900 mL). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography on silica gel (eluted withPet ether:EtOAc=50:1-5:1) to provide (2-amino-6-bromophenyl)methanol (10g, 54%): ¹H NMR (CDCl₃) δ 1.77 (s, 1H), 4.34 (s, 2H), 4.92 (s, 2H), 6.64(m, 1H), 6.95 (m, 2H).

Step B:3-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)aniline

To the solution of (2-amino-6-bromophenyl)methanol (3.02 g, 15 mmol) andimidazole (1.83 g, 27 mmol) in DMF (40 mL) was added TBSCl (3.39 g, 22.5mmol) in portions at about 0° C. Then the resulting mixture was stirredat rt overnight. The mixture was poured into H₂O (80 mL), extracted withMTBE (3×80 mL). The combined organic phase was washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (eluted withPet ether:EtOAc=15:1) to give3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)aniline (4.2 g, 89%): ¹HNMR (CDCl₃) δ 0.00 (s, 6H), 0.80 (s, 9H), 4.38 (s, 2H), 4.85 (s, 2H),6.48 (m, 1H), 6.79 (m, 2H).

Step C:3-(3-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-6-fluoroquinazolin-4(3)-one

The mixture of 3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)aniline(3.5 g, 11 mmol), 2-amino-5-fluoro-benzoic acid (1.7 g, 11 mmol) andCH(OMe)₃ (1.8 g, 16.5 mmol) in THF (30 mL) was heated at about 120° C.in a sealed tube overnight. The mixture was cooled to rt andconcentrated under reduced pressure. The residue was washed with EtOActo afford3-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-6-fluoroquinazolin-4(3H)-one(1.3 g, 25%): ¹H NMR (CDCl₃) δ 0.00 (d, J=8 Hz, 6H), 0.85 (s, 9H), 4.57(d, J=11.6 Hz, 1H), 4.98 (d, J=11.6 Hz, 1H), 7.35 (m, 1H), 7.43 (t, J=8Hz, 1H), 7.62 (m, 1H), 7.83 (m, 2H), 8.06 (m, 2H).

Step D:3-(2-(((tert-Butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-fluoroquinazolin-4(3H)-one

The mixture of3-(3-bromo-2-tert-butyldimethylsilyloxy)methyl)phenyl-6-fluoroquinazolin-4(3H)-one(4 g, 8.6 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]b[1,3,2]dioxaborolanyl (2.6 g, 10.4mmol), KOAc (1.7 g, 17.2 mmol) and Pd(dppf)Cl₂ (0.8 g) inDMSO/1,4-dioxane (8 mL: 40 mL) was heated to about 110° C. under N₂atmosphere for about 2 h. The mixture was cooled to rt, diluted withEtOAc (100 mL), filtered and the filtrate was washed with H₂O (30 mL)and brine (30 mL) successively. The organic phase was dried over Na₂SO₄,filtered and concentrated to afford the crude product which was purifiedby column chromatography on silica gel (Pet ether/EtOAc, 30:1 to 5:1) toprovide3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-fluoroquinazolin-4(3H)-one(1.7 g, 38%): ¹H NMR (CDCl₃) δ 0.00 (d, J=2 Hz, 6H), 0.92 (s, 9H), 1.52(s, 12H), 4.70 (d, J=1.6 Hz, 1H), 5.43 (d, J=1.6 Hz, 1H), 7.63 (m, 1H),7.70 (m, 2H), 7.93 (m, 1H), 8.16 (m, 3H).

Preparation #12: (R)-7-(Piperidin-3-yl)imidazo[1,2-a]pyrazin-8(7H)-onehydrochloride

Step A: (R)-tert-Butyl (1-benzylpiperidin-3-yl)carbamate

To a solution of (R)-tert-butyl piperidin-3-ylcarbamate (40.0 g, 0.2mol, 1.0 equiv) and TEA (22.22 g, 0.22 mol, 1.1 equiv) in DCM (500 mL)was added dropwise bromomethyl-benzene (37.62 g, 0.22 mol, 1.1 equiv) at0° C. After stirring overnight at about 25° C., the solution was dilutedwith DCM and washed with water. The organic layer was dried andevaporated to afford (R)-tert-butyl (1-benzylpiperidin-3-yl)carbamate(58.0 g, 100%), which was used to the next step without furtherpurification: ¹H NMR (CDCl₃) 7.15-7.26 (m, 5H), 4.92 (s, 1H), 3.67 (s,1H), 3.39 (s, 2H), 2.16-2.45 (m, 4H), 1.41-1.61 (m, 4H), 1.37 (s, 9H)

Step B: (R)-1-Benzylpiperidin-3-amine hydrochloride

To a solution of (R)-tert-butyl (1-benzylpiperidin-3-yl)carbamate (58.0g, 0.2 mol, 1.0 equiv) in MeOH (200 mL) was added HCl/MeOH (4.0 M, 200mL) and the mixture was stirred for about 2 h. The solvent was removedby vacuum to provide (R)-1-benzylpiperidin-3-amine hydrochloride (50 g):¹H NMR (MeOD) δ 7.64 (d, J=2.4 Hz, 2H), 7.50 (s, 3H), 4.42-4.52 (q, 2H),3.64-3.66 (d, J=10.8 Hz, 2H), 3.51-3.54 (d, J=12 Hz, 1H), 3.01-3.16 (m,2H), 2.20-2.22 (d, J=11.2 Hz, 1H), 2.00-2.11 (m, 2H), 1.66-1.74 (m, 1H)

Step C: (R)—N-(1-Benzylpiperidin-3-yl)-1H-imidazole-2-carboxamide

To a solution of 1H-imidazole-2-carboxylic acid (16.8 g, 0.15 mol) inDMF (500 mL) was added HATU (57 g, 0.15 mol) and the mixture was stirredfor about 2 h at rt. Then (R)-tert-butyl(1-benzylpiperidin-3-yl)carbamate (39.45 g, 0.15 mol) was added to thesolution and the mixture was stirred overnight. Additional1H-imidazole-2-carboxylic acid (5.2 g, 46 mmol) and HATU (17.6 g, 46mmol, 0.3 equiv) was added and the mixture was stirred at rt for 3 days.The solvent was removed and the residue was dissolved in EtOAc, washedwith water, dried and concentrated. The residue was purified by columnchromatograph on silica gel to provide crude(R)—N-(1-benzylpiperidin-3-yl)-1H-imidazole-2-carboxamide (50 g): LC/MS(Table 1, Method k) R_(t)=1.15 min; MS m/z: 285 (M+H)⁺.

Step D:(R)—N-(1-Benzylpiperidin-3-yl)-1-(2,2-diethoxyethyl)-1H-imidazole-2-carboxamide

A mixture of(R)-7-(1-benzylpiperidin-3-yl)imidazo[1,2-a]pyrazin-8(7H)-one (73.0 g,150 mmol, crude), 2-bromo-1,1-diethoxy-ethane (30 g, 150 mmol), K₂CO₃(41.4 g, 300 mmol) and KI (1 g) in DMF (500 mL) was heated to about 120°C. for 3 days. The solvent was removed. The residue was dissolved inDCM, washed with water, dried and evaporated to afford(R)—N-(1-benzylpiperidin-3-yl)-1-(2,2-diethoxyethyl)-1H-imidazole-2-carboxamide(30 g, 75 mmol) as an oil: LC/MS (Table 1, Method k) R_(t)=1.81 min; MSm/z: 401 (M+H)⁺.

Step E: (R)-7-(1-Benzylpiperidin-3-yl)imidazo[1,2-a]pyrazin-8(7H)-one

A mixture of(R)—N-(1-benzylpiperidin-3-yl)-1-(2,2-diethoxyethyl)-1H-imidazole-2-carboxamide(30.0 g, 75 mmol, crude) in 2N HCl (200 mL) was heated to refluxovernight. The solvent was removed and the residue was diluted withwater (50 mL) which was basified by saturated Na₂CO₃ to pH 10. Theaqueous phase was extracted with DCM, dried and evaporated. The residuewas purified by column chromatograph on silica gel to afford(R)-7-(1-benzylpiperidin-3-yl)imidazo[1,2-a]pyrazin-8(7H)-one (3.0 g,9.7 mmol): ¹H NMR (CDCl₃) δ 7.44 (s, 1H), 7.17-7.24 (m, 7H), 7.01-7.02(d, J=6 Hz, 1H), 5.00-5.05 (m, 1H), 3.45-3.47 (d, J=5.6 Hz, 2H),2.78-2.80 (m, 1H), 2.55-2.58 (m, 1H), 2.31-2.36 (m, 1H), 2.25 (s, 1H),1.81 (s, 1H), 1.16-1.69 (m, 3H)

Step F: (R)-tert-Butyl3-(8-oxoimidazo[1,2-a]pyrazin-7(8H)-yl)piperidine-1-carboxylate

To a solution of(R)-7-(1-benzylpiperidin-3-yl)imidazo[1,2-a]pyrazin-8(7H)-one (2.13 g,6.9 mmol) in MeOH (40 mL) was added (Boc)₂O (3.09 g, 13.8 mmol) and Pd/C(1.5 g). The mixture was hydrogenated under H₂ balloon overnight andthen filtrated. The filtrate was concentrated and purified by columnchromatograph on silica gel to afford (R)-tert-butyl3-(8-oxoimidazo[1,2-a]pyrazin-7(8H)-yl)piperidine-1-carboxylate (1.4 g,64%): ¹H NMR (MeOD) δ 7.69-7.70 (d, J=1.2 Hz, 1H), 7.52-7.54 (d, J=6.4Hz, 1H), 7.50 (s, 1H), 7.12-7.14 (d, J=6 Hz, 1H), 4.74-4.82 (m, 1H),4.12-4.15 (d, J=11.6 Hz, 1H), 4.04-4.05 (m, 1H), 3.05-3.11 (m, 1H), 2.83(s, 1H), 1.91-2.02 (m, 2H), 1.86-1.90 (m, 1H), 1.60-1.71 (m, 1H), 1.46(s, 9H)

Step G: (R)-7-(Piperidin-3-yl)imidazo[1,2-a]pyrazin-8(7H)-onehydrochloride

To a solution of (R)-tert-butyl3-(8-oxoimidazo[1,2-a]pyrazin-7(8H)-yl)piperidine-1-carboxylate (1.4 g,4.4 mmol) in MeOH (10 mL) was added HCl/MeOH (4 M, 10 mL) and themixture was stirred for about 1 h at rt. The solvent was removed toafford (R)-7-(piperidin-3-yl)imidazo[1,2-a]pyrazin-8(7H)-onehydrochloride (1.35 g, 100%): ¹H NMR (DMSO-d6) δ 10.06 (s, 1H), 9.67 (s,1H), 8.18-8.21 (m, 1H), 8.00-8.03 (m, 1H), 7.89-7.93 (m, 1H), 7.69-7.74(m, 1H), 5.12-5.18 (m, 1H), 3.20-3.34 (m, 3H), 2.82-2.90 (m, 1H),2.02-2.08 (m, 1H), 1.84-1.93 (m, 3H)

Preparation #13:(R)-7-(Piperidin-3-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H-onehydrochloride

Step A: (R)-tert-Butyl3-(8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)piperidine-1-carboxylate

To a solution of(R)-7-(1-benzylpiperidin-3-yl)imidazo[1,2-a]pyrazin-8(7H)-one (0.77 g,2.5 mmol) in MeOH (20 mL) was added (Boc)₂O (1.09 g, 5.0 mmol) andPd(OH)₂ (0.5 g). The mixture was hydrogenated under H₂ balloon overnightand then filtrated. The filtrate was evaporated and purified by columnchromatograph on silica gel to afford (R)-tert-butyl3-(8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)piperidine-1-carboxylate(0.5 g, 60%): ¹H NMR (MeOD) δ 7.16 (s, 1H), 7.06 (s, 1H), 4.22-4.33 (m,1H), 4.19-4.20 (m, 2H), 3.93-3.96 (m, 2H), 3.64-3.78 (m, 2H), 2.86-2.89(m, 1H), 2.61 (s, 1H), 168-1.79 (m, 3H), 1.47-1.53 (m, 1H), 1.46 (s,9H).

Step B:(R)-7-(Piperidin-3-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-onehydrochloride

To a solution of (R)-tert-butyl3-(8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)piperidine-1-carboxylate(0.5 g, 1.5 mmol, 1 equiv) in MeOH (5 mL) was added HCl/MeOH (4.0 M, 5mL) and the mixture was stirred for 1 h at rt. The solvent was removedto afford(R)-7-(piperidin-3-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-onehydrochloride (0.45 g, 100%): ¹H NMR (MeOD) δ 7.75-7.78 (q, J=9.6 Hz,2H), 4.66-4.74 (m, 1H), 4.56-4.59 (q, J=7.2 Hz, 2H), 3.99-4.03 (t, J=6Hz, 2H), 3.32-3.45 (m, 3H), 2.96-3.03 (m, 1H), 1.85-2.14 (m, 4H).

Preparation #14:(Z)-4-((3-(7-carbamoyl-1H-indol-4-yl)phenyl)amino)-4-oxobut-2-enoic acid

To a solution of 4-(3-aminophenyl)-1H-indole-7-carboxamide (0.25 g,0.995 mmol, Preparation #A.1), furan-2,5-dione (0.117 g, 1.19 mmol), andN-ethyl-N-isopropylpropan-2-amine (0.521 mL, 2.98 mmol) in DMF (10.0 mL)was added. The mixture is stirred at rt overnight. Solvent was removedunder high vacuum and the residue was purified by prep HPLC (Table 2,Method y) to provide(Z)-4-((3-(7-carbamoyl-1H-indol-4-yl)phenyl)amino)-4-oxobut-2-enoic acid(0.32 g, 92%) as a solid. LC/MS (Table 1, Method g) R_(t)=1.37 min; MSm/z 350 (M+H)⁺.

Preparation #15. tert-Butyl3-(7-carbamoyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

Step A. Methyl4-bromo-2-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-1-tosyl-1H-indole-7-carboxylate

To a mixture of methyl 4-bromo-2-iodo-1-tosyl-1H-indole-7-carboxylate (1g, 1.9 mmol, Preparation #1, Step D) in DME (20 mL)/water (5 mL) wasadded tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(0.72 g, 2.4 mmol), Na₂CO₃ (0.6 g, 5.6 mmol) and Pd(dppf)Cl₂ (0.2 g,0.28 mmol). The reaction mixture was stirred at rt for 10 h under N₂atmosphere. After filtering, the filtrate was concentrated under reducedpressure to give a residue, which was purified by column chromatographyon silica gel (eluted with hexanes:EtOAc=5:1) to give methyl4-bromo-2-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-1-tosyl-1H-indole-7-carboxylate(0.6 g, 56%) as yellow solid: ¹H NMR (CDCl₃) δ 7.68-7.56 (d, J=8.22 Hz,1H), 7.55-7.54 (m, 1H), 7.14-7.05 (m, 4H), 6.45-6.37 (m, 2H), 4.37-4.31(m, 2H), 4.05 (s, 3H), 3.89-3.84 (m, 2H), 2.38-2.34 (m, 3H), 1.53 (m,9H).

Step B:4-Bromo-2-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole-7-carboxylicacid

To a solution of methyl4-bromo-2-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-1-tosyl-1H-indole-7-carboxylate(2.5 g, 4.34 mmol) in THF (20 mL)/MeOH (5 mL)/water (5 mL) was addedLiOH.H₂O (2.5 g, 59.5 mmol) at rt. The reaction mixture was stirred atrt for about 3 h. The reaction was concentrated and residue wasacidified by addition of 2N HCl to about pH 5 and extracted with EtOAc(3×50 mL). The combined organic layer was dried and concentrated to givea solid, which was washed with EtOAc and MTBE to give4-bromo-2-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole-7-carboxylicacid (1 g, 56.5%) as white solid: ¹H NMR (CDCl₃) δ 9.84 (m, 1H),7.77-7.75 (t, J=5.6 Hz, 1H), 7.34-7.32 (d, J=8 Hz, 1H), 6.54-6.49 (d,J=16.8 Hz, 1H), 6.18-6.14 (d, J=18 Hz, 1H), 4.58-4.51 (d, J=30.4 Hz,2H), 4.38-4.32 (d, J=22 Hz, 2H), 1.54 (s, 9H).

Step C: tert-Butyl3-(4-bromo-7-carbamoyl-1H-indol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

To a solution of4-bromo-2-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole-7-carboxylicacid (1 g, 2. 5 mmol) in DMF (6 mL) was added PyBOP (2.6 g, 4.9 mmol),HOBt (0.75 g, 4.91 mmol), DIEA (1.7 mL, 9.82 mmol) and NH₄Cl (0.2 g, 3.7mmol). The reaction mixture was stirred at rt overnight. After quenchingwith water, the aqueous layer was extracted with EtOAc (3×25 mL). Thecombined organic layers were dried and concentrated under reducedpressure to give a residue, which was purified by prep-HPLC (Table 1,Method ad) to give tert-butyl3-(4-bromo-7-carbamoyl-1H-indol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(0.6 g, 54%) as white solid: ¹H NMR (CDCl₃) δ 10.42 (s, 1H), 7.26-7.25(m, 2H), 6.48 (s, 1H), 6.19-6.13 (d, J=22.4 Hz, 1H), 4.55-4.51 (d, J=16Hz, 2H), 4.37-4.32 (d, J=18 Hz, 2H), 1.54 (s, 9H).

Step D: tert-Butyl3-(7-carbamoyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

A solution of tert-butyl3-(4-bromo-7-carbamoyl-1H-indol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(0.6 g, 1.48 mmol),3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one(1 g, 2.95 mmol, WO 2011159857), K₂CO₃ (0.816 g, 5.91 mmol) andPd(dppf)Cl₂ (0.22 g, 0.3 mmol) in THF (20 mL)/MeOH (5 mL)/water (5 mL)was stirred at about 60° C. for about 2 h under N₂ atmosphere. Thesolvent was removed to give a residue, which was purified by columnchromatography on silica gel (eluted with hexanes:EtOAc=2:1) to givetert-butyl3-(7-carbamoyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(0.6 g, 72%) as a solid: ¹H NMR (MeOD) δ 10.44 (s, 1H), 8.40-8.38 (d,J=8 Hz, 1H), 8.15-8.10 (s, J=21.6 Hz, 1H), 7.83-7.81 (m, 2H), 7.59-7.35(m, 5H), 7.09-6.98 (m, 1H), 6.31-6.11 (m, 4H), 4.49-4.36 (m, 4H), 2.04(s, 3H), 1.51 (s, 9H).

Preparation #16. tert-Butyl4-(7-carbamoyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

Step A: tert-Butyl 2-(4-bromo-7-carbamoyl-1H-indol-2-yl)benzylcarbamate

To a solution of compound methyl4-bromo-2-iodo-1-tosyl-1H-indole-7-carboxylate (2.4 g, 6.58 mmol,Preparation #1) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2.0 g, 6.58 mmol) in THF (50 mL), MeOH (10 mL) and water (10 mL) wereadded Na₂CO₃ (2.1 g, 19.73 mmol) and Pd(dppf)Cl₂ (0.481 g, 0.658 mmol),the mixture was heated to about 80° C. for about 3 h. The resultingsolution was diluted with EtOAc (100 mL), and washed with water (30 mL).The organic phase was dried over Na₂SO₄, and concentrated under reducedpressure to give a crude product, which was purified by columnchromatography on silica gel (eluted with Pet ether:EtOAc=1:1) to givetert-butyl4-(4-bromo-7-carbamoyl-1H-indol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2 g, 72%) as a solid: ¹H NMR (DMSO-d6) δ 10.87 (s, 1H), 8.15 (s, 1H),7.59-7.57 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.27-7.25 (d, J=8.0 Hz, 1H),6.47 (s, 1H), 6.42 (s, 1H), 4.03 (s, 2H), 3.55 (s, 2H), 2.52 (s, 2H),1.41 (s, 9H).

Step B: tert-Butyl4-(7-carbamoyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of tert-butyl4-(4-bromo-7-carbamoyl-1H-indol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2 g, 4.76 mmol) and3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one(2.59 g, 7.14 mmol, WO 2011159857) in THF (40 mL), MeOH (10 mL) andwater (10 mL) were added Na₂CO₃ (1.513 g, 14.28 mmol) and Pd(dppf)Cl₂(0.348 g, 0.476 mmol). The mixture was heated to about 80° C. for about4 h. The resulting solution was diluted with EtOAc (100 mL), and washedwith water and brine (30 mL each). The organic phase was dried overNa₂SO₄, and concentrated to give a crude product, which was purified bycolumn chromatography on silica gel (eluted with Pet ether:EtOAc=1:1) togive tert-butyl4-(7-carbamoyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(1.4 g, 51%) as a solid: ¹H NMR (CDCl₃) 10.43 (s, 1H), 8.42-8.40 (d,J=7.6 Hz, 1H), 8.15 (s, 1H), 7.85-7.83 (m, 2H), 7.61-7.59 (m, 1H),7.49-7.45 (m, 3H), 7.37-7.34 (m, 1H), 7.04-7.01 (m, 1H), 6.20 (s, 2H),3.65 (s, 2H), 2.55 (s, 2H), 2.00 (s, 3H), 1.76 (s, 2H), 1.50 (s, 9H).

Preparation #17:1-(Methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine

A solution of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(4.03 g, 13.03 mmol, Carbocore) in HCl (4 M in dioxane, 19.55 mL, 78mmol) was stirred at ambient temperature for about 2 h. The solution wasconcentrated under reduced pressure then dissolved in DCM (20.05 mL) andTEA added (12.72 mL, 91 mmol). The mixture was cooled to about 0° C. andmethanesulfonyl chloride (1.83 mL, 23.5 mmol) added dropwise. Themixture was stirred at ambient temperature for about 2 h. To the mixturewas added 1N HCl (60 mL) and the organic layer was extracted. Theorganic layer was with saturated aqueous sodium bicarbonate (60 mL),dried over MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was trituated with a mixture of EtOAc and heptanes, filtered anddried (1.477 g). The filtrate was concentrated and residue was trituatedwith a mixture of EtOAc and heptanes, filtered and dried to get secondlot (0.940 g). Lots were combined to obtain1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(2.41 g, 64%). LC/MS (Table 1, Method a) R_(t)=2.18 min: MS m/z: 288(M+H)⁺.

Preparation #18:4-Bromo-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide

A flask containing1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(0.446 g, 1.55 mmol, Preparation #17),4-bromo-2-iodo-1H-indole-7-carboxamide (0.54 g, 1.48 mmol, Preparation#1), sodium carbonate (0.470 g, 4.44 mmol) and1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.108 g,0.148 mmol) was purged with nitrogen. A mixture of THF (15.0 mL), MeOH(2.10 mL), and water (2.10 mL) was added. The mixture was stirred forabout 2 h at about 70° C. The mixture was filtered through Celite©rinsing with EtOAc and concentrated under reduced pressure. The residuewas trituated with DCM, filtered, washed with DCM and EtOAc to afford asolid (0.315 g). The filtrate was concentrated and purified by columnchromatography on silica gel (40-100% EtOAc/heptane). The resultingresidue was triturated with DCM, filtered and dried to afford a solid(0.125 g). The solids were combined to obtain4-bromo-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide(0.44 g, 75%). LC/MS (Table 1, Method a) R_(t)=1.92 min: MS m/z: 400(M+H)⁺.

Preparation #19:N-Methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazole-2-carboxamide

ToN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazole-2-carboxamide(502 mg, 1.46 mmol, Preparation #4) in THF (10 mL) was added sodiumhydride (70.0 mg, 1.75 mmol) at about 0° C. and stirred for about 25min. To the mixture was added iodomethane (0.363 mL, 5.83 mmol) at about0° C. The reaction mixture was brought to rt and then stirred at rt forabout 18 h. To mixture was added water, extracted twice with DCM andlayers separated. Combined organic layers were evaporated and theresidue was purified using normal phase chromatography to provideN-methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazole-2-carboxamide(0.406 g, 59%). LC/MS (Table 1, Method f) R_(t)=1.97 min: MS m/z: 359(M+H)⁺.

Preparation #20.(R)-1-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15mmol) in DMF (25.8 mL) was added sodium hydride (0.206 g, 5.15 mmol).The mixture was stirred at rt for about 10 min under nitrogen.(S)-(+)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (1.62 g,5.67 mmol) was added and the mixture was stirred at about 90° C.overnight under an nitrogen atmosphere. The reaction was cooled to rt,and partitioned between EtOAc and water. The aqueous layer wasre-extracted with EtOAc (2×) and the organics were combined, washed withwater, brine, dried over anhydrous MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel with EtOAc/hexanes (30-75%) to provide(R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.66 g, 42%): LC/MS (Table 1, Method f) R_(t)=1.41 min; MS m/z: 309(M+H)⁺.

Preparation #21.(S)-1-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.2mmol) in DMF (25.8 mL) was added sodium hydride (0.206 g, 5.15 mmol).The mixture was stirred at rt for about 10 min under nitrogen.(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate(1.62 g, 5.67 mmol) was added and the mixture was stirred at about 90°C. overnight under an nitrogen atmosphere. The reaction was cooled tort, partitioned between EtOAc and water. The aqueous layer wasre-extracted with EtOAc (2×) and the organics were combined, washed withwater, brine, dried over anhydrous MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified by was columnchromatography on silica gel with EtOAc/hexanes (30-75%) to provide(S)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.83 g, 52%): LC/MS (Table 1, Method f) R_(t)=1.35 min; MS m/z: 251(M−(CH₃)₂CHO+H)⁺.

Preparation #22:N-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide

To a vial was added3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.30 g, 1.37mmol) in DCM (10 mL), and DIEA (0.72 mL, 4.11 mmol). The mixture wascooled to about 0° C. and acryloyl chloride (0.122 mL, 1.51 mmol) wasadded while stirring. The mixture was stirred for about 20 min whilewarming to rt. The mixture was diluted with and additional DCM (10 mL)washed with water (2×10 mL), filtered through a Biotage phase separatorand concentrated under a warm stream of nitrogen to provideN-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide(0.375 g, 100%): LC/MS (Table 1, Method f) R_(t)=1.70 min; MS m/z: 274(M+H)⁺.

Preparation #23: N-(trans-4-Hydroxypiperidin-3-yl)thiazole-2-carboxamide

Step A. Benzyl 4-(hydroxyimino)piperidine-1-carboxylate

A mixture of benzyl 4-oxopiperidine-1-carboxylate (10 g, 42.9 mmol),NH₂OH HCl (5.9 g, 86 mmol) and K₂CO₃ (11.8 g, 86 mmol) in EtOH (45 mL)was heated at about 50° C. for about 0.5 h. Then the solvent was removedunder reduced pressure. Water and EtOAc were added to the residue. Theaqueous phase was extracted with EtOAc (3×75 mL). The organic layer waswashed with brine and dried over Na₂SO₄, filtered and concentrated toprovide benzyl 4-(hydroxyimino)piperidine-1-carboxylate (10 g, 94%). ¹HNMR (CDCl₃) δ 2.36 (br, 2H), 2.63 (br, 2H), 3.63-3.58 (m, 4H), 5.15 (s,2H), 7.36-7.35 (m, 5H), 9.05 (br, 1H).

Step B. Benzyl 4-((tosyloxy)imino)piperidine-1-carboxylate

To a solution of benzyl 4-(hydroxyimino)piperidine-1-carboxylate (12.2g, 49.1 mmol) in pyridine (75 mL) was added TsCl (12.2 g, 64 mmol)slowly at about 0° C. The reaction mixture was stirred at thistemperature for about 0.5 h and stirred at rt for another 2 h. Then thesolvent was removed under reduced pressure. Water and EtOAc were addedto the residue. The aqueous phase was extracted with EtOAc (3×125 mL).The organic layer was washed with brine and dried over Na₂SO₄. Thesolvent was concentrated to give the crude product which was purified bycolumn chromatography on silica gel (Pet ether:EtOAc=15:1) to providebenzyl 4-((tosyloxy)imino)piperidine-1-carboxylate (5 g, 25.3%): ¹H NMR(CDCl₃) δ 2.37 (br, 2H), 2.44 (s, 3H), 2.63 (br, 2H), 3.62-3.55 (m, 4H),5.13 (s, 2H), 7.35-7.32 (m, 7H), 7.85 (d, J=8.0 Hz, 2H).

Step C. Benzyl 3-amino-4-oxopiperidine-1-carboxylate hydrochloride

Na (28.6 mg, 1.243 mmol) was added to EtOH (6.5 mL) and the mixture wasstirred until the Na was completely dissolved. MgSO₄ (0.98 g) was addedto the solution, then benzyl 4-((tosyloxy)imino)piperidine-1-carboxylate(0.5 g, 1.242 mmol) was added to the solution at about 0° C. After thereaction mixture was heated at about 30° C. for about 2 h, the mixturewas filtered and 1 N HCl (6.5 mL) was added to the filtration. Thefiltration was stirred at rt for about 0.5 h and concentrated. Theresidue was mixed with EtOH (3 mL) and filtered. The filtration wasconcentrated to give crude benzyl 3-amino-4-oxopiperidine-1-carboxylatehydrochloride (200 mg, 0.702 mmol): 1H NMR (MeOD) δ=7.33 (m, 5H), 5.12(br. s., 2H), 3.75-3.95 (m, 1H), 3.6-3.7 (m, 1H), 3.5 (m, 2H), 3.1-3.2(m, 1H), 1.95-2.10 (m, 1H), 1.7-1.8 (m, 1H).

Step D. Benzyl 4-oxo-3-(thiazole-2-carboxamido)piperidine-1-carboxylate

A solution of thiazole-2-carboxyic acid mg, 14.6 mmol) and HATU (723 mg,1.9 mmol) in DMF (20 mL) was stirred at rt for 0.5 h, then DIEA (945 mg,7.31 mmol) and benzyl 3-amino-4-oxopiperidine-1-carboxylatehydrochloride (500 mg, 1.76 mmol) was added to the mixture. The reactionsolution was stirred at rt for about 4 h. Water was added to themixture, extracted with EtOAc (3×45 mL). The combined organic layer waswashed with brine several times, dried over Na₂SO₄, filtered andconcentrated to give the crude product which was purified by Prep-HPLC(Table 1, Method ai) to provide benzyl4-oxo-3-(thiazole-2-carboxamido)piperidine-1-carboxylate (82 mg, 12%).¹H NMR (CDCl₃) δ 2.68-2.62 (br, 2H), 2.93-2.86 (m, 1H), 3.16 (br, 1H),4.7-5.9 (br, 2H), 5.08-5.05 (m, 1H), 5.31-5.22 (m, 2H), 7.43-7.38 (m,5H), 7.60 (q, J=1.2 Hz, 1H), 7.92-7.90 (m, 1H), 8.08 (s, 1H).

Step E. trans-Benzyl4-hydroxy-3-(thiazole-2-carboxamido)piperidine-1-carboxylate

To a solution of benzyl4-oxo-3-(thiazole-2-carboxamido)piperidine-1-carboxylate (6.9 g, 19.2mmol) in MeOH (50 mL) was added NaBH₄ (0.726 g, 0.019 mmol) in batchesand the mixture was stirred at rt for about 0.5 h. Then water (50 mL)was added to the reaction mixture and extracted with DCM (3×60 mL). Theorganic layer was washed with brine and dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product which waspurified by column chromatography on silica gel to provide trans-benzyl4-hydroxy-3-(thiazole-2-carboxamido)piperidine-1-carboxylate (3 g, 43%).¹H NMR (MeOD) δ 1.56-1.51 (m, 1H), 2.00 (t, J=5.2 Hz, 1H), 3.10-2.97 (m,2H), 3.85-3.75 (m, 2H), 4.16-3.99 (m, 1H), 4.21-4.20 (m, 1H), 5.12 (s,2H), 7.34-7.31 (m, 5H), 7.85 (q, J=3.2 Hz, 1H), 7.94 (t, J=3.2 Hz, 1H).

Step F. N-(trans-4-Hydroxypiperidin-3-yl)thiazole-2-carboxamide

To a stirred solution of trans-benzyl4-hydroxy-3-(thiazole-2-carboxamido)piperidine-1-carboxylate (0.7 g,1.937 mmol) in MeCN (15 mL) was added TMSI (1.55 g, 775 mmol) slowly atabout 0° C., then the mixture was stirred at rt for about 1 h. Water waspoured into the mixture and MeCN was removed under reduced pressure. 1 NHCl was added to the residue and the mixture was extracted with MTBE(3×30 mL). Then the aqueous phase was basified with NaOH (3 N) to aboutpH=12 and extracted with DCM (6×45 mL). The organic phase was washedwith brine and dried over Na₂SO₄, filtered and concentrated to give thecrude product which was purified by Prep-TLC (1:1 MeOH/DCM) to provideN-(trans-4-hydroxypiperidin-3-yl)thiazole-2-carboxamide (50 mg, 11%): ¹HNMR (MeOD) δ 1.86-1.77 (m, 1H), 2.28-2.22 (m, 1H), 3.29-309 (m, 2H),3.56-3.44 (m, 2H), 4.84-3.90 (m, 2H), 7.88 (q, J=3.2 Hz, 1H), 7.97 (q,J=3.2 Hz, 1H).

Preparation #24:4-Bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide

Step A.4-Bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylicacid

To a solution of methyl4-bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate(10 g, 19.6 mmol, Preparation #10, step B) in MeOH (150 mL), THF (300mL) and water (150 mL) was added lithium hydroxide hydrate (12 g, 286mmol). The resulting mixture was heated at about 45° C. for about 3 h.Then the mixture was concentrated under reduced pressure to remove mostsolvent, the residue was dissolved in water. The aqueous mixture wasacidified by addition of aqueous HCl (1N) to about pH 6. The precipitatewas filtered, and the solid was dried to give4-bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylicacid (9.1 g, 94%) as a solid: ¹H NMR (CDCl₃) δ 13.44 (br, 1H), 7.57-7.51(m, 2H), 7.09 (s, 1H), 5.95 (s, 2H), 3.35-3.11 (t, J=8.0 Hz, 2H),0.87-0.83 (t, J=8.0 Hz, 2H), 0.00 (s, 9H).

Step B.4-Bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide

A solution of4-bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylicacid (8 g, 16 mmol), EDCI (4.6 g, 24 mmol) and HOBt (3.7 g, 24 mmol) inTHF (240 mL) and DCM (280 mL) was stirred at rt for about 1 h. Thereaction mixture was then bubbled with NH₃ gas for 15 min and stirred atrt overnight. Then the mixture was concentrated and partitioned betweenaqueous NaHCO₃ and EtOAc. The organic phase was washed with brine, driedand concentrated to give a residue, which was suspended in Pet ether andthe solid was collected by filtration to provide4-bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide(7.2 g, 90%) as a white solid: ¹H NMR (CDCl₃) δ 7.36-7.33 (m, 1H),7.26-7.24 (d, J=8.0 Hz, 1H), 7.05 (s, 1H), 6.08 (br, 1H), 5.82 (br, 1H)5.82 (s, 2H), 3.48-3.41 (m, 2H), 0.90-0.86 (m, 2H), 0.00 (s, 9H).

Preparation #25:4-(Difluoromethyl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(oxetan-3-yl)benzamide

A solution of 4-(difluoromethyl)benzoic acid (0.089 g, 0.519 mmol,Oakwood) in DCM (3.46 mL) under nitrogen was treated with sulfurousdichloride (0.075 mL, 1.037 mmol) and 1 drop DMF. The mixture wasstirred at about 35° C. for about 16 h. The reaction was concentratedunder reduced pressure, triturated residue with heptane, andconcentrated. The residue was dissolved in DCM (3.46 mL) and addedN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-amine(0.100 g, 0.346 mmol, prepared using H from2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[Combi-Blocks] and 3-oxetanone[(Molbridge]) and TEA (0.193 mL, 1.383mmol). The mixture was stirred at ambient temperature for about 4 h thendiluted with DCM (10 mL) and quenched with saturated aqueous sodiumbicarbonate (10 mL). The organics were combined and washed with 30 mLsaturated aqueous sodium bicarbonate. The organic layer was dried overMgSO₄, filtered and concentrated under reduced pressure to give thecrude product which was purified by column chromatography on silica gel(0-40% EtOAc/heptane) to provide a yellow oil that solidified uponstanding to afford4-(difluoromethyl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(oxetan-3-yl)benzamide(0.092 g, 60%). LCMS (Table 1, Method a) R_(t)=2.51 min: MS m/z: 444(M+H)⁺.

Preparation #26:2-Methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol

To a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g,10.31 mmol) in 2,2-dimethyloxirane (11.96 mL, 134 mmol) in a 30 mLmicrowave vial was added cesium carbonate (0.521 g, 1.60 mmol). Themixture was heated in a microwave oven at about 120° C. for about 30min. The reaction was cooled and filtered. The resulting solution wasevaporated to dryness to give2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-olas a white solid. (2.7 g, 99%); (Table 1, Method g) R_(t)=1.34 min.; MSm/z: 267 (M+H)⁺

Preparation #27: 4-Fluoro-2-iodo-1-tosyl-1H-indole-7-carbonitrile

Step A. 4-Fluoro-1-tosyl-1H-indole-7-carbonitrile

To a solution of 4-fluoro-1H-indole-7-carbonitrile (5.3 g, 33.1 mmol,Sinova) in DMF (92 mL) was added NaH (2.0 g, 49.6 mmol) at 0° C. underN₂ atmosphere and stirred for about 30 min. Then TsCl (9.46 g, 49.6mmol) was added to the above mixture and stirred at rt for about 5 h.The mixture was poured into saturated aqueous NH₄Cl solution (200 mL),extracted with EtOAc (100 mL×3). The combined organic phase was washedwith brine, dried over Na₂SO₄, filtered and concentrated to afford thecrude product which was washed with MTBE to provide4-fluoro-1-tosyl-1H-indole-7-carbonitrile (7 g, 67.3%) as a solid: ¹HNMR (CDCl₃) δ 2.39 (s, 3H), 6.86 (d, J=4 Hz, 1H), 6.99 (t, J=8.4 Hz,1H), 7.33 (d, J=8.4 Hz, 2H), 7.62 (m, 1H), 7.84 (d, J=3.6 Hz, 1H), 7.92(d, J=8.4 Hz, 2H).

Step B. 4-Fluoro-2-iodo-1-tosyl-1H-indole-7-carbonitrile

Freshly prepared LDA (67 mL, 38.2 mmol) was added dropwise to a solutionof 4-fluoro-1-tosyl-1H-indole-7-carbonitrile (10 g, 31.8 mmol) in THF(50 mL) at about −78° C. After the addition was complete, the mixturewas stirred for another 45 min. Then a solution of I₂ (9.69 g, 38.2mmol) in THF (50 mL) was added dropwise to the mixture at about −78° C.After the addition, the mixture was stirred for about another 1 h. Thesolution was poured into saturated aqueous Na₂S₂O₃ (400 mL), extractedwith EtOAc (100 mL×3). The combined organic phase was washed with brine,dried over Na₂SO₄, filtered and concentrated to afford the crude productwhich was washed with EtOAc to give4-fluoro-2-iodo-1-tosyl-1H-indole-7-carbonitrile (8.5 g, 61%) as asolid: ¹H NMR (CDCl₃) δ2.45 (s, 3H), 7.01 (t, J=8.4 Hz, 1H), 7.20 (s,1H), 7.33 (d, J=8.4 Hz, 2H), 7.64 (m, 1H), 8.05 (d, J=8.4 Hz, 2H).

Step C. tert-Butyl4-(7-cyano-4-fluoro-1-tosyl-1H-indol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of 4-fluoro-2-iodo-1-tosyl-1H-indole-7-carbonitrile (0.2g, 6.3 mol) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2.05 g, 6.63 mmol) in the mixture of THF (20 mL), MeOH (4 mL) and water(4 mL) was added Na₂CO₃ (2.108 g, 19.89 mmol) and PdCl₂(dppf) DCM (0.541g, 0.663 mmol). The mixture was heated at about 80° C. for about 3 h.Then the reaction was cooled and diluted with EtOAc (30 mL) and washedwith water (3×10 mL). The organic phase was dried over Na₂SO₄, filteredand concentrated under reduced pressure to give crude product which waspurified by column chromatography on silica gel (eluted with Petether:EtOAc=10:1) to give tert-butyl4-(7-cyano-4-fluoro-1-tosyl-1H-indol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2.5 g, 76%): ¹H NMR (CDCl₃) δ 1.25 (s, 2H), 1.52 (s, 9H), 2.38 (s, 3H),3.63 (t, J=5.6 Hz, 2H), 4.09 (d, J=2.8 Hz, 2H), 5.83 (d, J=2.8 Hz, 1H),6.56 (s, 1H), 7.04 (t, J=8.4 Hz, 1H), 7.20 (d, J=8.0 Hz, 2H), 7.48 (s,2H), 7.68 (q, J=5.2 Hz, 1H).

Step D.4-Fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)-1-tosyl-1H-indole-7-carbonitrilehydrochloride

To a solution of tert-butyl4-(7-cyano-4-fluoro-1-tosyl-1H-indol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(2.7 g, 5.45 mmol) in EtOAc (30 mL) was added dropwise HCl/EtOAc (30 mL)at about 0° C., then the reaction was stirred at rt for about 3 h. Themixture was filtered and the filter cake was washed with EtOAc to give4-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)-1-tosyl-1H-indole-7-carbonitrilehydrochloride (1.96 g, 83%): ¹H NMR (MeOD) δ 2.35 (s, 3H), 2.78 (s, 2H),3.48 (t, J=5.6 Hz, 2H), 3.94 (s, 2H), 6.04 (s, 1H), 6.86 (s, 1H),7.23-7.29 (m, 3H), 7.43 (d, J=8.0 Hz, 2H), 7.84 (t, J=5.2 Hz, 1H).

Step E.4-Fluoro-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-tosyl-1H-indole-7-carbonitrile

To a solution of tert-butyl4-(7-cyano-4-fluoro-1-tosyl-1H-indol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(1.96 g, 4.54 mmol) and TEA (1.84 g, 18.2 mmol) in DCM (30 mL) was addedMsCl (0.623 g, 5.44 mmol), then the mixture was stirred at rt for about24 h. Then water was added to the mixture and the reaction mixture wasextracted with DCM (3×30 mL). The combined organic layer was washed withbrine and dried over Na₂SO₄, filtered and concentrated under reducedpressure to give4-fluoro-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-tosyl-1H-indole-7-carbonitrile(1.35 g, 63%) which was used in the next step without any furtherpurification. LC/MS (Table 1, Method f) R_(t)=2.15 min; MS m/z: 474(M+H)⁺.

Preparation #28: 3-Bromo-N-(cyanomethyl)benzenesulfonamide

To a cooled (0° C.) solution of 2-aminoacetonitrile hydrochloride (0.50g, 5.40 mmol) in pyridine (27.0 mL) was slowly added3-bromobenzene-1-sulfonyl chloride (0.779 mL, 5.40 mmol). The mixturewas slowly warmed to rt and stirred for about 16 h. The mixture wasconcentrated under reduced pressure and the residue was dissolved in DCMand washed with 1N HCl, saturated sodium bicarbonate, brine and filteredthrough a Biotage Phase separator after each wash step. The organicswere concentrated under reduced pressure afford the crude product. Thecrude product was purified by column chromatography on silica gel elutedEtOAc/heptane (0-40%) to provide3-bromo-N-(cyanomethyl)benzenesulfonamide (0.61 g, 41%): ¹H NMR(DMSO-d6): δ 8.73 (br, 1H), 7.98 (t, J=1.79, 1H), 7.91 (d, J=8.02, 1H),7.84 (d, J=8.02, 1H), 7.60 (t, J=7.92, 1H), 4.18 (s, 2H).

Preparation #29:4-Cyclopropyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide

To a solution of2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.350g, 1.501 mmol) and HATU (0.856 g, 2.252 mmol) in DCM (2 mL) was addedTEA (0.628 mL, 4.50 mmol) and 4-(difluoromethyl)benzoic acid (0.336 g,1.952 mmol). The mixture was stirred at about rt for about 18 h. Themixture was evaporated and the resulting residue was purified by silicagel chromatography eluting with a gradient of 30-50% EtOAc in hexane togive4-cyclopropyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide(0.52, 89%); LC/MS (Table 1, Method c) R_(t)=2.10 min.; MS m/z: 388(M+H)⁺

Preparation #30: (R)-6-Fluoro-2-(piperidin-3-yl)isoindolin-1-onehydrochloride

Step A: Methyl 5-fluoro-2-methylbenzoate

To a solution of 5-fluoro-2-methylbenzoic acid (20 g, 0.13 mol) inanhydrous MeOH (200 mL) was added SOCl₂ (38.9 g, 0.33 mol) dropwise. Theresulting mixture was stirred at rt overnight. The solvent wasevaporated to dryness to give methyl 5-fluoro-2-methylbenzoate (24 g,99%) as an oil. ¹H NMR (CDCl₃): δ 7.62-7.59 (d, J=9.6 Hz, 1H), 7.21-7.18(d, J=8.4 Hz, 1H), 7.12-7.09 (d, J=8.0 Hz, 1H), 3.89 (s, 3H), 2.55 (s,3H).

Step B: Methyl 2-(bromomethyl)-5-fluorobenzoate

To a solution of methyl 5-fluoro-2-methylbenzoate (24 g, 0.14 mol) inCCl₄ (250 mL) was added NBS (28 g, 0.16 mol) and BPO (1.7 g, 7.2 mmol).The reaction mixture was heated to reflux for about 18 h. The hotreaction mixture was filtered and the filtrate was concentrated in vacuoto give methyl 2-(bromomethyl)-5-fluorobenzoate (35 g, crude), which wasused in next step reaction directly without further purification. H NMR(DMSO-d6): δ 7.67-7.60 (m, 2H), 7.48-7.45 (d, J=8.4 Hz, 1H), 4.98 (s,2H), 3.86 (s, 3H).

Step C: (R)-tert-Butyl3-(6-fluoro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate

To a solution of methyl 2-(bromomethyl)-5-fluorobenzoate (35 g) in MeCN(400 mL) was added K₂CO₃ (39 g, 0.29 mol) and3-(R)-amino-piperidine-1-carboxylic acid tert-butyl ester (20 g, 0.10mol). The reaction mixture was heated to reflux for about 3 h and thenstirred at rt overnight. The resulting suspension was filtered and thefiltrate was concentrated under vacuum to give the residue which wasdissolved in EtOAc (300 mL) and washed with brine (2×100 mL). Theorganic phase was dried over Na₂SO₄ and concentrated. The resultingresidue was purified by column chromatography on silica gel (elutingwith 15:1 petroleum ether:EtOAc) to give (R)-tert-butyl3-(6-fluoro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate (12 g, 25%) asa solid: ¹H NMR (CDCl₃): δ 7.46-7.43 (d, J=7.6 Hz, 1H), 7.35-7.32 (d,J=8.0 Hz, 1H), 7.20-7.14 (m, 1H), 4.36-4.26 (m, 2H), 4.18 (m, 1H),4.06-3.89 (m, 2H), 2.99-2.93 (m, 1H), 2.75 (s, 1H), 1.95-1.92 (m, 1H),1.74-1.65 (m, 2H), 1.56-1.54 (m, 1H), 1.39 (s, 9H).

Step D: (R)-6-Fluoro-2-(piperidin-3-yl)isoindolin-1-one hydrochloride

To a solution of (R)-tert-butyl3-(6-fluoro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate (12 g, 0.036mol) in DCM (100 mL) was added 1M HCl in MeOH (150 mL). The resultingmixture was stirred at rt overnight. The reaction mixture wasconcentrated under vacuum to give(R)-6-fluoro-2-(piperidin-3-yl)isoindolin-1-one hydrochloride B (9.0 g,100%) as a solid. LCMS (ESI+): m/z 235 (M+H)⁺, R_(t): 1.90 min.; ¹H NMR(D₂O): δ 7.43-7.40 (m, 1H), 7.28-7.21 (m, 2H), 4.39-4.37 (d, J=5.6 Hz,2H), 4.33-4.31 (m, 1H), 3.38-3.34 (m, 2H), 3.12-3.06 (t, J=12.0 Hz, 1H),2.88-2.85 (m, 1H), 2.00-1.95 (m, 2H), 1.87-1.77 (m, 2H).

Preparation #31: (R)-3-(Piperidin-3-yl)quinazolin-4(3H)-one

Step A: (R)-tert-Butyl3-(4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate

To a solution of 2-aminobenzoic acid (7.5 g, 54.7 mmol) and3-(R)-amino-piperidine-1-carboxylic acid tert-butyl ester (10.9 g, 54.7mmol) in THF (20 mL) was added triethyl orthoformate (8.1 g, 54.7 mmol).The reaction mixture was heated to about 110° C. in a sealed tubeovernight. After cooling to rt, the mixture was diluted with water andextracted with EtOAc. The combined organic phase was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure togive a residue, which was purified by column chromatography on silicagel (eluting with 10:1 petroleum ether:EtOAc) to give (R)-tert-butyl3-(4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate (7.5 g, 42%) as ayellow solid. ¹H NMR (CDCl₃): δ 8.34-8.32 (m, 1H), 8.11 (s, 1H),7.80-7.71 (m, 2H), 7.55-7.51 (m, 1H), 4.75 (br, 1H), 4.23-4.11 (br, 2H),3.24-3.18 (t, 1H), 2.87 (br, 1H), 2.18-1.98 (m, 2H), 1.91-1.87 (br, 1H),1.77-1.71 (m, 1H), 1.48 (s, 9H).

Step B: (R)-3-(Piperidin-3-yl)quinazolin-4(3H)-one

The reaction solution of (R)-tert-butyl3-(4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate (12.5 g, 36 mmol)in 1M HCl/MeOH (150 mL) was stirred at about rt for about 2.5 h. Themixture was filtered. The solid was washed with EtOAc and dried to give(R)-3-(piperidin-3-yl)quinazolin-4(3H)-one (10 g, 98%) as a white solid.LCMS (ESI+): m/z 248 (M+H)⁺, RT: 1.90 min. ¹H NMR (D₂O): δ 8.55-8.54 (d,J=2.8 Hz, 1H), 7.80-7.77 (dd, J=3.2 Hz, J=2.8 Hz, 1H), 7.68-7.60 (m,2H), 4.95-4.89 (m, 1H), 3.61-3.57 (m, 1H), 3.46-3.43 (d, J=12.4 Hz, 1H),3.37-3.31 (t, 1H), 3.04-2.97 (m, 1H), 2.24-2.14 (m, 3H), 1.94-1.87 (m,1H).

Preparation #32: (R)-6-Fluoro-3-(piperidin-3-yl)quinazolin-4(3H)-onehydrochloride

Step A: (R)-tert-Butyl3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate

The reaction solution of 2-amino-5-fluorobenzoic acid (7.5 g, 48.4mmol), 3-(R)-1-amino-piperidine-1-carboxylic acid tert-butyl ester (9.68g, 48.4 mmol) and triethyl orthoformate (7.2 g, 48.4 mmol) in THF (20mL) was heated to about 110° C. in a sealed tube overnight. Aftercooling to rt, the mixture was diluted with water. The aqueous layer wasextracted with EtOAc. The combined organic phase was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure togive a residue, which was purified by column chromatography on silicagel (eluting with 10:1 petroleum ether:EtOAc) to give (R)-tert-butyl3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate (6.25 g,37%) as a solid. ¹H NMR (CDCl₃): δ 8.08 (s, 1H), 7.97-7.95 (m, 1H),7.76-7.72 (m, 1H), 7.53-7.48 (m, 1H), 4.74 (br, 1H), 4.24-4.12 (br, 2H),3.24-3.19 (t, 1H), 2.89 (br, 1H), 2.14-2.10 (m, 2H), 2.04-2.01 (m, 1H),1.91-1.71 (m, 1H), 1.49 (s, 9H).

Step B: (R)-6-Fluoro-3-(piperidin-3-yl)quinazolin-4(3H)-onehydrochloride

A solution of (R)-tert-butyl3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate (12.5 g,36 mmol) in 1M HCl/MeOH (150 mL) was stirred at about rt about for about2.5 h. The mixture was filtered and the solid was washed with EtOAc anddried to give (R)-6-fluoro-3-(piperidin-3-yl)quinazolin-4(3H)-onehydrochloride (10 g, 98%) as a solid. LC/MS (ESI+): m/z 248 (M+H)⁺, RT:1.90 min. ¹H NMR (D₂O): δ 8.55-8.54 (d, J=2.8 Hz, 1H), 7.80-7.77 (dd,J=3.2 Hz, J=2.8 Hz, 1H), 7.68-7.60 (m, 2H), 4.95-4.89 (m, 1H), 3.61-3.57(m, 1H), 3.46-3.43 (d, J=12.4 Hz, 1H), 3.37-3.31 (t, 1H), 3.04-2.97 (m,1H), 2.24-2.14 (m, 3H), 1.94-1.87 (m, 1H).

Preparation #33:7-Cyclopropyl-5-fluoro-3-(piperidin-3-yl)quinazolin-4(3H)-onehydrochloride

Step A: tert-Butyl3-(7-bromo-5-fluoro-4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate

To a solution of 2-amino-4-bromo-6-fluorobenzoic acid (7 g 3 mol,prepare according to WO 2011075699) and 3-amino-piperidine-1-carboxylicacid tert-butyl ester (6.6 g, 0.033 mol) in THF (50 mL) was addedtriethyl orthoformate (6.6 g, 0.044 mol). The reaction mixture washeated at about 110° C. in a sealed tube overnight. After cooling toabout rt, the mixture was diluted with water. The aqueous was extractedwith EtOAc. The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to give aresidue, which was purified by column chromatography on silica gel(eluting with 50:1 petroleum ether:EtOAc) to give tert-butyl3-(7-bromo-5-fluoro-4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate(6.4 g, 50%) as a solid. ¹H NMR (CDCl₃): δ 8.1 (s, 1H), 7.54-7.52 (dd,J=2.4 Hz, 1H), 7.35-7.32 (dd, J=2.8 Hz, 1H), 4.7 (br, 1H), 4.2-4.16 (br,1H), 4.07-4.03 (br, 1H), 3.24-3.18 (t, 1H), 2.92-2.89 (br, 1H),2.11-2.09 (br, 1H), 1.98-1.96 (br, 1H), 1.89-1.85 (br, 1H), 1.74-1.64(br, 1H), 1.45 (s, 9H).

Step B: tert-Butyl3-(7-cyclopropyl-5-fluoro-4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate

To a mixture of tert-butyl3-(7-bromo-5-fluoro-4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate(20 g, 0.047 mol), Pd(OAc)₂ (0.526 g, 0.002 mol), tricyclohexylphosphine(1.31 g, 0.005 mol), anhydrous K₃PO₄ (50 g, 0.236 mol) and water (40 mL)in toluene (200 mL) was added cyclopropylboronic acid (6.06 g, 0.07mol). The reaction mixture was heated to reflux overnight under N₂.After cooling to rt, the mixture was diluted with water. The aqueouslayer was extracted with EtOAc. The combined organic phase was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give a residue, which was purified by column chromatographyon silica gel (eluting with 50:1 petroleum ether:EtOAc) to givetert-butyl3-(7-cyclopropyl-5-fluoro-4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate(15 g, 83%) as a solid. ¹H NMR (CDCl₃): δ 7.96 (s, 1H), 7.07-7.04 (dd,J=2.4 Hz, 1H), 6.71-6.67 (dd, J=2.4 Hz, 1H), 4.68-4.65 (br, 1H), 4.16(br, 1H), 4.06-4.02 (br, 1H), 3.37-3.33 (m, 1H), 3.08-3.02 (m, 1H),2.82-2.76 (br, 1H), 2.06-2.01 (m, 1H), 1.90-1.69 (m, 2H), 1.64-1.60 (m,1H), 1.40 (s, 9H), 1.20-1.06 (m, 2H), 0.712-0.608 (m, 2H).

Step C: 7-Cyclopropyl-5-fluoro-3-(piperidin-3-yl)quinazolin-4-(3H)-onehydrochloride

A solution of tert-butyl3-(7-cyclopropyl-5-fluoro-4-oxoquinazolin-3(4H)-yl)piperidine-1-carboxylate(15 g, 0.039 mmol) in 1M HCl/MeOH (150 mL) was stirred at about rt forabout 2.5 h. The mixture was filtered, the solid was washed with EtOAcand dried to give7-cyclopropyl-5-fluoro-3-(piperidin-3-yl)quinazolin-4(3H)-onehydrochloride (10 g, 91%) as a solid. LCMS (ESI+): m/z 288 (M+H)⁺,R_(t): 2.916 min. ¹H NMR (D₂O): δ 8.56 (s, 1H), 6.99-6.96 (m, 1H),6.85-6.82 (dd, J=1.6 Hz, 1H), 4.87-4.83 (m, 1H), 3.54-3.51 (m, 1H),3.41-3.38 (d, 1H), 3.24-3.18 (t, 1H), 2.96-2.89 (t, 1H), 2.84-2.81 (m,1H), 2.13-2.09 (m, 3H), 1.89-1.82 (m, 1H), 0.96-094 (br, 2H), 0.61 (br,2H).

Preparation #34:2-(Benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Step A: 1-(Benzyloxy)-4-bromo-2-nitrobenzene

To a solution of 4-bromo-2-nitrophenol (5 g, 22.9 mmol) in acetone (100mL) was added (bromomethyl)benzene (4.7 g, 27.5 mmol) and K₂CO₃ (6.3 g,45.9 mmol). The mixture was refluxed overnight. After cooling to rt, themixture was filtered. The filtrate was concentrated under reducedpressure to give a residue, which was washed with TBME to give1-(benzyloxy)-4-bromo-2-nitrobenzene (6.3 g, 89%): ¹H NMR (CDCl₃) δ 8.00(d, J=2.2 Hz, 1H), 7.60 (dd, J=2.6, 8.8 Hz, 1H), 7.49-7.31 (m, 5H), 7.03(d, J=8.8 Hz, 1H), 5.24 (s, 2H).

Step B: 2-(Benzyloxy)-bromoaniline

To a solution of 1-(benzyloxy)-4-bromo-2-nitrobenzene (2 g, 6.5 mmol) inEtOH (80 mL) and water (20 mL) was added iron (1.8 g, 32.5 mmol) andNH₄Cl (1.7 g, 32.5 mmol). The resulting mixture was refluxed for 3 h.The mixture was filtered. The filtrate was diluted with water andextracted with EtOAc. The organic layer was concentrated to give2-(benzyloxy)-5-bromoaniline (1.6 g, 89%): ¹H NMR (CDCl₃) δ 7.51-7.30(m, 5H), 6.86 (d, J=2.2 Hz, 1H), 6.83-6.76 (m, 1H), 6.74-6.66 (m, 1H),5.07 (s, 2H), 3.91 (br, 2H)

Step C:2-(Benzyloxy-5-(4,4,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

To a solution of 2-(benzyloxy)-5-bromoaniline (2.0 g, 7.19 mmol) in DMSO(30 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.2 g, 8.6mmol), Pd(dppf)Cl₂ (0.53 g, 0.72 mmol) and potassium acetate (2.1 g,21.6 mmol). The mixture was stirred at 80° C. overnight under N₂. Aftercooling to rt, the mixture was diluted with water and extracted withEtOAc. The organic layer was concentrated and purified by column to give2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(1.5 g, 64%): ¹H NMR (CDCl₃) δ 7.55-7.29 (m, 5H), 7.23-7.12 (m, 2H),6.86 (d, J=7.9 Hz, 1H), 5.11 (s, 2H), 3.80 (br, 2H), 1.32 (s, 12H).

Preparation #35:3-(Benzyloxy)-5-(4,4,5,5-tetramethyl-13,2-dioxaborolan-2-yl)aniline

Step A: 3-Bromo-5-nitrophenol

To a solution of 1-bromo-3-methoxy-5-nitrobenzene (19 g, 82 mmol) in DCM(800 mL) was added dropwise BBr₃ (27.9 mL, 295 mmol) in DCM (120 mL).The resulting mixture was heated to reflux overnight. After cooling inice-water, the mixture was diluted by addition of water. Then themixture was washed with brine. The organic phase was dried over Na₂SO₄,concentrated under reduced pressure to give a residue, which waspurified by column chromatography on silica gel to give3-bromo-5-nitrophenol (8 g, 44%) as a solid: H NMR (CDCl₃) δ 7.89 (s,1H), 7.57 (s, 1H), 7.27 (s, 1H), 5.27 (s, 1H).

Step B: 1-(Benzyloxy)-3-bromo-5-nitrobenzene

To a solution of 3-bromo-5-nitrophenol in acetone (50 mL) was added(bromomethyl)benzene (2.4 g, 13.8 mmol) and K₂CO₃ (3.2 g, 22.9 mmol).The resulting mixture was heated to reflux overnight. The mixture wasfiltered. The filtrate was concentrated under reduced pressure to give aresidue, which was washed with TBME to give1-(benzyloxy)-3-bromo-5-nitrobenzene (1.3 g, 37%) as a solid: ¹H NMR(CDCl₃) δ 8.00 (s, 1H), 7.78-7.77 (m, 1H), 7.64-7.40 (m, 6H), 5.15 (s,2H).

Step C: 3-(Benzyloxy)-5-bromoaniline

To a solution of 1-(benzyloxy)-3-bromo-5-nitrobenzene (1.3 g, 4.2 mmol)in EtOH (30 mL) and water (7.5 mL) was added iron (1.2 g, 21.1 mmol) andNH₄Cl (1.1 g, 21.1 mmol). The mixture was heated to reflux overnight.The mixture was filtered. The filtrate was concentrated under reducedpressure to give a residue, which was diluted by addition of water andextracted by EtOAc. The organic layer was concentrated under reducedpressure to give 3-(benzyloxy)-5-bromoaniline (1 g, 85%): ¹H NMR (CDCl₃)δ 7.33-7.31 (m, 5H), 6.48 (s, 1H), 6.39 (s, 1H), 6.14 (s, 1H), 4.92 (s,2H), 3.63 (br, 2H).

StepD:3-(Benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

To a solution of 3-(benzyloxy)-5-bromoaniline (1 g, 3.6 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.1 g, 4.3mmol) in DMSO (1 mL) was added Pd(dppf)Cl₂ (0.26 g, 0.36 mmol) andpotassium acetate (1.1 g, 10.8 mmol). The mixture was heated to about80° C. overnight under N₂. After cooling to rt, the mixture was dilutedby addition of water and extracted by EtOAc. The organic layer wasconcentrated under reduced pressure to give a residue, which waspurified by column chromatography on silica gel to give3-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1g, 86%) as a solid: ¹H NMR (CDCl₃) δ 7.43-7.31 (m, 5H), 6.87 (s, 1H),6.77 (s, 1H), 6.43-6.42 (m, 1H), 5.05 (s, 2H), 3.64 (br, 2H), 1.34 (s,12H).

Preparation #36: 4-(Benzyloxy)-1-bromo-2-nitrobenzene

To a solution of 4-bromo-3-nitrophenol (2 g, 9.17 mmol, Preparation#S.1) in acetone (50 mL) was added BnBr (1.9 g, 11.0 mmol) and K₂CO₃(2.5 g, 18.4 mmol). The mixture was filtered. The filtrate wasconcentrated under reduced pressure to give a residue, which was washedwith TBME to give 4-(benzyloxy)-1-bromo-2-nitrobenzene (2.6 g, 92%): ¹HNMR (CDCl₃) δ 7.62 (d, J=8.8 Hz, 1H), 7.48 (d, J=2.6 Hz, 1H), 7.45-7.35(m, 5H), 7.07 (dd, J=2.9, 9.0 Hz, 1H), 5.12 (s, 2H).

Preparation #37: 4-(Benzyloxy)-1-bromo-2-nitrobenzene

Step A: Methyl2-(2-methoxy-2-oxoethyl)-1-(4-methoxybenzyl)-1H-pyrrole-3-carboxylate

A flask was charged with dimethyl 3-oxopentanedioate (77.0 g, 442 mmol),(4-methoxyphenyl)methanamine (60.1 mL, 460 mmol) and anhydrous NaOAc(72.5 g, 884 mmol) in dioxane (100 mL). The reaction mixture was stirredat about rt for about 30 min, then heated to about 50° C. and stirredfor about 16 h. The reaction mixture was cooled to rt and dioxane (250mL) was added. 2-chloroacetaldehyde (51.9 mL, 442 mmol) was added via adropping funnel. After about 7 h additional 2-chloroacetaldehyde (17.4g, 221 mmol) was added and stirred for about 16 h. Additional2-chloroacetaldehyde (17.4 g, 221 mmol) was added and stirred for about5 h, more 2-chloroacetaldehyde was added (25.9 mL, 221 mmol), the finalportion of 2-chloroacetaldehyde (25.9 mL, 221 mmol) was added afterabout 2 h and left to stir for about 72 h. NaOAc (36.3 g, 442 mmol) wasadded and the solution and stirred for about 16 h. The reaction mixturewas cooled under an ice bath and ice-water added to it (about 500 mL).The mixture was extracted with DCM (850 mL). The organic layer waswashed with water (4×700 mL). The organic layer was dried over MgSO₄,filtered and concentrated to give a viscous oil. The crude material waspurified via flash chromatography (using heptane for 3 column volumes,0-25% EtOAc/heptane over 4 column volumes, 20-35% over 4 columnvolumes). The pure fractions were combined and concentrated and minimalEt₂O added to precipitate out a first batch of product which wascollected via filtration. The filtrate was combined with the impurefractions, concentrated under vacuum and recrystallized from isopropanolto give a solid which was collected via filtration and combined with thefirst batch of product. The material was dried in a vacuum oven at about70° C. for about 16 h to give methyl2-(2-methoxy-2-oxoethyl)-1-(4-methoxybenzyl)-1H-pyrrole-3-carboxylate(28.5 g, 20%): LC/MS (Table 1, Method as) R_(t)=2.20 min; MS m/z: 318(M+H)⁺.

Step B: Methyl2-(1-amino-3-methoxy-3-oxoprop-1-en-2-yl)-1-(4-methoxybenzyl)-1H-pyrrole-3-carboxylate

A flask was charged with NaH (23.3 g, 582 mmol) and THF (500 mL). Themixture was cooled to about 0° C. and methyl2-(2-methoxy-2-oxoethyl)-1-(4-methoxybenzyl)-1H-pyrrole-3-carboxylate(28 g, 88 mmol) was added portion wise. The internal temperaturemeasured below 10° C. during the addition. The suspension was stirred atabout 0° C. for about 1 h. Methyl formate (7.62 mL, 124 mmol) was added.The reaction mixture was allowed to warm to rt and was stirred for about16 h. Additional methyl formate (1.09 mL, 17.6 mmol) was added and themixture stirred at rt for about 4 to 5 h, at which point all thestarting material was consumed. The reaction was cooled on ice andquenched by the addition of MeOH (5 mL), and water was added carefullyuntil effervescence stopped. The mixture was then acidified to pH ofabout 1 with aqueous 6N HCl, while keeping the flask on an ice bath. Thereaction mixture was diluted with EtOAc (100 mL) and water (100 mL). Theaqueous layer was separated and extracted with EtOAc (3×50 mL). Thecombined organic layers were then dried over MgSO₄ and filtered. Thesolvent was evaporated to yield an oil consisting of two layers. Thethinner top layer was clear and was separated using a pipette anddiscarded. The remaining bottom layer was the crude intermediate, methyl2-(1-hydroxy-3-methoxy-3-oxoprop-1-en-2-yl)-1-(4-methoxybenzyl)-1H-pyrrole-3-carboxylate.A flask was charged with this crude methyl2-(1-hydroxy-3-methoxy-3-oxoprop-1-en-2-yl)-1-(4-methoxybenzyl)-1H-pyrrole-3-carboxylate(30 g, 87 mmol) and MeOH (300 mL). Ammonium acetate (33.5 g, 434 mmol)was added and the reaction mixture was refluxed for about 4 h andstirred at about 60° C. for about 72 h. The reaction mixture wasconcentrated under vacuum and diluted with water (200 mL) and EtOAc (200mL). Part of the product precipitated out and was collected byfiltration. The organic layer was separated. The aqueous layer wasextracted again with EtOAc (2×80 mL). The combined organic layers weredried over MgSO₄, filtered, and concentrated. The residue was suspendedin Et₂O (200 mL) and stirred for about 10 min and filtered to collectthe product. This batch was combined with the previous precipitate anddried in a vacuum oven at about 70° C. for about 4 h to give methyl2-(1-amino-3-methoxy-3-oxoprop-1-en-2-yl)-1-(4-methoxybenzyl)-1H-pyrrole-3-carboxylate(25.7 g, 82%): LC/MS (Table 1, Method as) R_(t)=1.88 min; MS m/z: 345(M+H)⁺.

Step C: Methyl1-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate

A flask was charged with methyl2-(1-amino-3-methoxy-3-oxoprop-1-en-2-yl)-1-(4-methoxybenzyl)-1H-pyrrole-3-carboxylate(24.6 g, 71.4 mmol) and t-BuONa (6.87 g, 71.4 mmol) in DMA (100 mL). Thesolution was heated at about 150° C. for about 10 min, and cooled to rt.The solution was then poured onto ice-water (250 mL) and diluted withEtOAc (200 mL). The mixture was stirred at rt for about 45 min. Theprecipitate that formed was filtered and washed with water, then driedin a vacuum oven at about 70° C. for about 16 h to yield methyl1-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate(18.9 g, 85%): LC/MS (Table 1, Method as) R_(t)=1.76 min; MS m/z: 313(M+H)⁺.

Step D: Methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate

A mixture of methyl1-(4-methoxybenzyl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate(24 g, 76 mmol) in phenyl phosphorodichloridate (30.8 mL, 206 mmol) washeated at about 150° C. for about 30 min. LCMS showed completeconversion to mixture of ester and acid. The reaction mixture was cooledto about 0° C. and 50% aqueous NaOH was added slowly until pH of about7. The reaction mixture was extracted with DCM (3×100 mL). The organiclayers were combined and concentrated under reduced pressure. Theresidue was suspended in Et₂O (100 mL), stirred at about 30° C. forabout 1 h, cooled to rt and filtered. The filtrate was concentrated togive crude methyl 4-chloro-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (22.5 g, 75%) as a black oil. A mixture ofthis crude methyl4-chloro-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxylate(21.76 g, 65.8 mmol) and triflic anhydride (7.50 mL, 44.4 mmol) in TFA(50 mL) was stirred at about 50° C. for about 16 h. The reaction mixturewas cooled to rt and added to ice cold NaHCO₃ solution. Aqueous NaOH wasslowly added to adjust the pH to about 9. The solid was filtered andsonicated in Et₂O. The precipitate was filtered of and the filtrate wasconcentrated to give methyl4-chloro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (9.4 g, 68%): LCMS(Table 1, Method a) R_(t)=1.83 min; MS m/z: 211 (M+H)⁺.

Preparation #38: Methyl4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-methyl-1H-indole-7-carboxylate

Step A: 1-tert-Butyl 7-methyl4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-methyl-1H-indole-1,7-dicarboxylate

To a solution of 1-tert-butyl 7-methyl4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-iodo-1H-indole-1,7-dicarboxylate(2.0 g, 3.5 mmol, Preparation #Y.1) in THF (35 mL) was added Zn (Me)₂ (1Min hexane, 21.04 mL, 21.04 mmol). The mixture was degassed usingnitrogen and Pd(dppf)Cl₂(0.257 g, 0.351 mmol) was added in one portionand stirred at rt for about 19 h. The reaction was warmed to about 45°C. and stirred for about 22 h. The reaction mixture was carefullyquenched by the addition of saturated aqueous NaHCO₃ (50 mL) and dilutedwith EtOAc (50 mL) and brine (20 mL). The layers were separated and theaqueous phase was extracted with EtOAc (2×50 mL). The combined organicextracts were washed with brine, dried over MgSO₄, filtered,concentrated under reduced pressure and purified by columnchromatography on silica gel (0-50% EtOAc/heptane) to provide1-tert-butyl 7-methyl4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-methyl-1H-indole-1,7-dicarboxylate(1.45 g, 79%): LCMS (Table 1, Method ba) R_(t)=3.02 min; MS m/z: 476(M+H)⁺.

Step B: Methyl4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-methyl-1H-indole-7-carboxylate

A solution of 1-tert-butyl 7-methyl4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-methyl-1H-indole-1,7-dicarboxylate(1.40 g, 3.05 mmol) in MeOH (7 mL) was added to a microwave reactionvial and the solution was heated to about 120° C. for about 30 min. Thereaction mixture was adsorbed onto silica gel and purified using silicagel chromatography (0-50% EtOAc/heptane) to give methyl4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-methyl-1H-indole-7-carboxylate(1 g, 86%): LCMS (Table 1, Method as) R_(t)=2.58 min; MS m/z: 359(M+NH₄).

Preparation #39: Methyl4-(1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridin-3-yl)-1-tosyl-1H-indole-7-carboxylate

A flask was charged with methyl4-(1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridin-3-yl)-1-tosyl-1H-indole-7-carboxylate(2.00 g, 3.92 mmol, prepared using A from Preparation #1, step B withtert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate)in THF (39.2 mL). The solution was cooled to about −71° C. LDA (1Msolution in hexanes/THF, 5.88 mL, 5.88 mmol) was added drop wise overabout 5 min while maintaining the temperature below −65° C. The solutionwas stirred at about −72° C. for about 45 min. CH₃I (0.367 mL, 5.88mmol) was added. The mixture was stirred at about −70° C. for a further2.5 hours, and then quenched with a saturated aqueous Na₂CO₃ solution(150 mL). The mixture was extracted with EtOAc (2×200 mL) and DCM (1×100mL). The combined organic layers were dried over Na₂SO₄, filtered,concentrated under reduced pressure and purified by columnchromatography on silica gel (25-75% EtOAc/heptane) to provide methyl4-(1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridin-3-yl)-1-tosyl-1H-indole-7-carboxylate(1.67 g, 57%, 70% purity): LCMS (Table 1, Method as) R_(t)=2.88 min; MSm/z: 542 (M+NH₄).

Preparation #40: tert-butyl3-((7-carbamoyl-2-iodo-1H-indol-4-yl)(methyl)amino)azetidine-1-carboxylate

Step A: Methyl4-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-2-iodo-1-tosyl-1H-indole-7-carboxylate

To a solution of methyl4-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-1-tosyl-1H-indole-7-carboxylate(4.00 g, 7.79 mmol, prepared using T from Preparation #1, step C withtert-butyl-3-aminoazetidine-1-carboxylate and J. with CH₃I) in THF (60mL) at about −78° C. was added slowly LDA (2M solution in THF, 5.84 mL,11.7 mmol). The reaction was stirred at about −78° C. for about 1 h anda solution of 12 (2.97 g, 11.7 mmol) in THF (10 mL) was added slowly andthe reaction stirred at about −78° C. for about 4 h. The cooling bathwas removed to warm the reaction to rt and the reaction was quenched bythe addition of saturated aqueous Na₂S₂O₃ (120 mL), extracted withadditional EtOAc (2×150 mL) and washed with brine (2×150 mL). Thecombined organics were dried with anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude product, methyl4-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-2-iodo-1-tosyl-1H-indole-7-carboxylate(4.1 g, 80%): LC/MS (Table 1, Method aa) R_(t)=1.87 min; MS m/z: 640(M+H)⁺.

StepB:4-((1-(tert-Butoxycarbonyl)azetidin-3-yl)(methyl)amino)-2-iodo-1H-indole-7-carboxylicacid

To a solution of methyl4-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-2-iodo-1-tosyl-1H-indole-7-carboxylate(15.5 g, 24.2 mmol) in MeOH (75 mL):THF (75 mL):water (30 mL) was addedKOH (9.52 g, 170 mmol). The mixture was stirred at about 60° C. forabout 16 h, cooled, and acidified with aqueous 2N HCl. It was extractedwith EtOAc (2×350 mL) and washed with brine (2×300 mL). The combinedorganics were dried with anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give the crude product4-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-2-iodo-1H-indole-7-carboxylicacid (11.4 g, 99%): LC/MS (Table 1, Method aa) R_(t)=1.86 min; MS m/z:416 (M+H-tBu)⁺.

Step C: tert-Butyl3-((7-carbamoyl-2-iodo-1H-indol-4-yl)(methyl)amino)azetidine-1-carboxylate

4-((1-(tert-Butoxycarbonyl)azetidin-3-yl)(methyl)amino)-2-iodo-1H-indole-7-carboxylicacid (13.7 g, 29.1 mmol), HOBt (8.90 g, 58.1 mmol) and EDC (11.2 g, 58.1mmol) were dissolved in DMF (260 mL) and DIEA (25.4 mL, 145 mmol) wasadded. The mixture was stirred at rt for about 10 min and NH₄Cl (12.4 g,233 mmol) was added. The mixture was stirred at rt for about 16 h andsaturated aqueous NH₄Cl (1 L) was added. The solid was collected byfiltration, washed with water, and dried to give the crude producttert-butyl3-((7-carbamoyl-2-iodo-1H-indol-4-yl)(methyl)amino)azetidine-1-carboxylate(13.4 g, 97%): LC/MS (Table 1, Method aa) R_(t)=1.81 min; MS m/z: 471(M+H)⁺.

Preparation #41:4-(Azetidin-3-yl(methyl)amino)-2-(tetrahydrofuran-3-yl)-1H-indole-7-carboxamide

A reaction vial was charged with tert-butyl3-((7-carbamoyl-2-iodo-1H-indol-4-yl)(methyl)amino)azetidine-1-carboxylate(0.050 g, 0.11 mmol, Preparation #40), (Z)-but-2-ene-1,4-diol (0.014 g,0.16 mmol), NaHCO₃ (10.7 mg, 0.128 mmol) and PdCl₂ (1.885 mg, 10.63μmol) in NMP (1.2 mL). The mixture was purged with nitrogen and heatedat about 130° C. for about 1 h. It was extracted with EtOAc (2×20 mL)and washed with brine (2×20 mL). The combined organics were dried overanhydrous Na₂SO₄, filtered, concentrated under reduced pressure andpurified by Prep TLC (EtOAc) to give crude tert-butyl3-((7-carbamoyl-2-(2,3-dihydrofuran-3-yl)-1H-indol-4-yl)(methyl)amino)azetidine-1-carboxylate(0.028 g, 39%). A mixture of tert-butyl3-((7-carbamoyl-2-(2,3-dihydrofuran-3-yl)-1H-indol-4-yl)(methyl)amino)azetidine-1-carboxylate(0.055 g, 0.081 mmol) in DCM (1.5 mL) was stirred at about 0° C. in anice bath. Triethylsilane (0.014 g, 0.12 mmol) was added and thenBF₃.OEt₂ (0.015 mL, 0.122 mmol) was added drop wise. The mixture wasstirred at about 0° C. for about 1 h and quenched with a saturatedaqueous solution of Na₂CO₃ to a pH of about 8 then filtered. Thefiltrate was purified by Prep HPLC (Table 1, method bc) to give4-(azetidin-3-yl(methyl)amino)-2-(tetrahydrofuran-3-yl)-1H-indole-7-carboxamide(0.008 mg, 28%): LC/MS (Table 1, Method av) R_(t)=1.03 min; MS m/z: 315(M+H)⁺.

Preparation #42: Methyl4-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-2-(3-hydroxyoxetan-3-yl)-1-tosyl-1H-indole-7-carboxylate

To a cold solution of methyl4-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-1-tosyl-1H-indole-7-carboxylate(0.80 g, 1.56 mmol, prepared using T from Preparation #1, step C withtert-butyl-3-aminoazetidine-1-carboxylate and J. with CH₃I) in THF (12mL) at about −78° C. was added slowly LDA (2M solution in THF, 1.168 mL,2.336 mmol). The reaction was stirred at about −78° C. for about 1 h,then a solution of oxetan-3-one (0.168 g, 2.34 mmol) in THF (1 mL) wasadded slowly and the reaction mixture was stirred at about −78° C. forabout 4 h. The cooling bath was removed and the reaction was quenchedwith saturated aqueous NH₄Cl solution. The mixture was extracted withEtOAc (2×50 mL) and washed with brine (2×50 mL). The combined organicswere dried over anhydrous Na₂SO₄, filtered, concentrated under reducedpressure and purified by Prep-TLC (1:1 EtOAc/pet. Et₂O) to give methyl4-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-2-(3-hydroxyoxetan-3-yl)-1-tosyl-1H-indole-7-carboxylate(0.55 g, 59%): LC/MS (Table 1, Method av) R_(t)=1.67 min; MS m/z: 586(M+H)⁺.

Preparation #43: tert-Butyl2-(7-cyano-1-tosyl-1H-indol-4-yl)morpholine-4-carboxylate

Step A: 4-Bromo-1-tosyl-1H-indole-7-carbonitrile

A round bottom flask was charged with 4-bromo-1H-indole-7-carbonitrile(4.50 g, 20.4 mmol) and THF (75 mL). The solution was cooled to about 0°C. followed by the addition of NaH (60% dispersion in mineral oil, 1.22g, 30.5 mmol). The solution was stirred at about 0° C. for about 40 minfollowed by the addition of 4-methylbenzene-1-sulfonyl chloride (4.66 g,24.4 mmol). The ice bath was removed and the mixture was stirred at rtfor about 15 h. The mixture was poured onto ice water (˜150 mL) and theproduct was extracted with EtOAc (4×75 mL). The combined extracts werewashed with water (75 mL), dried over MgSO₄, filtered and concentratedunder reduced pressure to give 4-bromo-1-tosyl-1H-indole-7-carbonitrile(5.74 g, 75%): ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (d, J=3.9 Hz, 1H),7.97-7.89 (m, 2H), 7.80-7.64 (m, 2H), 7.56-7.42 (m, 2H), 7.00 (d, J=3.8Hz, 1H), 2.38 (s, 3H).

Step B: 1-Tosyl-4-vinyl-1H-indole-7-carbonitrile

A round bottom flask was charged with4-bromo-1-tosyl-1H-indole-7-carbonitrile (8.54 g, 22.8 mmol), Na₂CO₃(7.24 g, 68.3 mmol) and PdCl₂(dppf) (1.665 g, 2.276 mmol) followed bythe addition of THF (70.2 mL): MeOH (10.03 mL): water (10.03 mL). Thereaction mixture was purged with N₂ for about 15 min,4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.63 mL, 27.3 mmol) wasadded and the mixture was heated to about 70° C. for about 5 h. Themixture was cooled to rt and DCM (75 mL) and water (50 mL) were added.The layers were separated and the aqueous layer was extracted with DCM(50 mL). The combined extracts were dried over MgSO₄, filtered,concentrated under reduced pressure and passed through a plug of silicagel, eluting with DCM, and concentrated under vacuum. The residue wassuspended in a mixture of Et₂O/EtOAc, filtered and then washed theprecipitate with a small amount of EtOAc/Et₂O. The material thusobtained was dried in vacuum oven to give1-tosyl-4-vinyl-1H-indole-7-carbonitrile (5.62 g, 77%): LC/MS (Table 1,Method as) R_(t)=2.57 min; MS m/z: 323 (M+H)⁺.

Step C: 4-(Oxiran-2-yl)-1-tosyl-1H-indole-7-carbonitrile

To a suspension of 1-tosyl-4-vinyl-1H-indole-7-carbonitrile (0.40 g,1.241 mmol) in dioxane (16 mL) and water (8 mL) was added AcOH (0.0710mL, 1.24 mmol). The mixture was cooled to about 0° C. NBS (0.243 g, 1.36mmol) was added in one portion. The reaction was allowed to warm to rtand stirred for about 2 h. NaOH (2M aqueous solution, 8.0 mL, 16 mmol)was added in one portion. The solid formed was collected by filtration,washed with water and dried in a vacuum oven at about 60° C. for about16 h to give 4-(oxiran-2-yl)-1-tosyl-1H-indole-7-carbonitrile (0.29 g,68%): LC/MS (Table 1, Method as) R_(t)=2.36 min; MS m/z: 339 (M+H)⁺.

Step C:4-(1-Hydroxy-2-((2-hydroxyethyl)amino)ethyl)-1-tosyl-1H-indole-7-carbonitrile

To a suspension of 4-(oxiran-2-yl)-1-tosyl-1H-indole-7-carbonitrile(0.285 g, 0.841 mmol) in IPA (8 mL) was added TEA (0.586 mL, 4.21 mmol)followed by 2-aminoethanol (0.253 mL, 4.21 mmol). The mixture was heatedat about 75° C. for about 3 h and concentrated under reduced pressure.The residue was partitioned between EtOAc and water. The mixture wasextracted with EtOAc (2×10 mL). The combined organic layers were driedover Na₂SO₄, filtered, concentrated and dried under a vacuum pump togive4-(1-hydroxy-2-((2-hydroxyethyl)amino)ethyl)-1-tosyl-1H-indole-7-carbonitrile(0.39 g, 94%): LC/MS (Table 1, Method as) R_(t)=1.53 min; MS m/z: 400(M+H)⁺.

Step D: tert-Butyl(2-(7-cyano-1-tosyl-1H-indol-4-yl)-2-hydroxyethyl)(2-hydroxyethyl)carbamate

To a solution of4-(1-hydroxy-2-((2-hydroxyethyl)amino)ethyl)-1-tosyl-1H-indole-7-carbonitrile(0.336 g, 0.673 mmol) in EtOAc (3 mL) was added DIEA (0.176 mL, 1.01mmol) followed by drop wise addition of a solution of di-tert-butyldicarbonate (0.220 g, 1.01 mmol) in EtOAc (1 mL) at rt. THF (1 mL) wasadded to help solubilize the mixture and stirred at rt for about 2 h.Additional DIEA (0.060 mL, 0.34 mmol) and di-tert-butyl dicarbonate(0.073 g, 0.34 mmol) were added. The mixture was stirred at rt for aboutanother 2 h. The solvent was removed under reduced pressure and purifiedby flash chromatography (25-50% EtOAc/heptane) then by HPLC (Table 1,Method bd) to give tert-butyl(2-(7-cyano-1-tosyl-1H-indol-4-yl)-2-hydroxyethyl)(2-hydroxyethyl)carbamate(0.25 g, 74%): LC/MS (Table 1, Method as) R_(t)=2.22 min; MS m/z: 500(M+H)⁺.

Step E: tert-Butyl2-(7-cyano-1-tosyl-1H-indol-4-yl)morpholine-4-carboxylate

To a vial charged withtert-butyl-(2-(7-cyano-1-tosyl-1H-indol-4-yl)-2-hydroxyethyl)(2-hydroxyethyl)carbamate(0.50 g, 1.0 mmol) and PPh₃ (0.315 g, 1.20 mmol) in toluene (10 mL) atabout 0° C. was added TEA (0.367 mL, 2.63 mmol) followed by addition ofDCAD (0.441 g, 1.20 mmol). The solution was stirred at about 0° C. forabout 5 min and then stirred at about rt for about 16 h. Additional PPh₃(0.131 g, 0.500 mmol) and DCAD (0.184 g, 0.500 mmol) were added at rtand the mixture was stirred at about rt for about 6 h. The reactionmixture was filtered and the filtrate was concentrated and purified byflash chromatography (0-30% EtOAc/heptane) to give tert-butyl2-(7-cyano-1-tosyl-1H-indol-4-yl)morpholine-4-carboxylate (0.41 g, 84%):LC/MS (Table 1, Method as) R_(t)=2.72 min; MS m/z: 499 (M+H₂O)⁺.

Preparation #44: 2-Iodo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine

Step A: 2-Nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine

A mixture of (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (4.0 g,12 mmol) [Princeton] in NMP (7.7 mL) was heated at about 130° C. forabout 16 h. The mixture was diluted with DCM and washed with water andbrine. The organic layer was dried, concentrated and purified bychromatography on silica gel (0-5% MeOH/DCM) to give2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1, 4]oxazine (1 g, 49%): ¹H NMR(400 MHz, DMSO-d₆) δ 6.88 (s, 1H), 4.83 (s, 2H), 4.24 (t, J=5.2 Hz, 2H),4.13 (dd, J=5.9, 4.6 Hz, 2H).

Step B: 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine

A flask was charged with Pd/C (10 wt %, 0.755 g, 0.709 mmol) undernitrogen before the addition of a solution of2-nitro-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (4.0 g, 24 mmol) inEtOAc (59.1 mL) and MeOH (59.1 mL). The reaction stirred at rt for about16 h. The reaction mixture was filtered through a plug of Celite® andthe filtrate was concentrated under reduced pressure to afford6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine (3.2 g, 97%): LC/MS(Table 1, Method as) R_(t)=0.61 min; MS m/z: 140 (M+H)⁺.

Step C: 2-Iodo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine

A 50 mL round-bottom flask was charged with6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-amine (1.5 g, 11 mmol) andconcentrated HCl (2.43 mL, 29.6 mmol). The mixture was cooled to about0° C. A solution of NaNO₂ (0.707 g, 10.2 mmol) in water (10 mL) wasadded and the reaction stirred for about 15 min. A solution of KI (2.86g, 17.3 mmol) in water (10 mL) was added carefully and the reaction wasstirred at about 0° C. for about 1 h and stirred at rt for about 30 min.The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL)and then separated from the aqueous layer. The solution was purified viachromatography on silica gel (0-50% EtOAc/heptane) to give2-iodo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (0.996 g, 37%): LC/MS(Table 1, Method as) R_(t)=1.58 min; MS m/z: 251 (M+H)⁺.

Preparation #45: Methyl4-chloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate

Step A: Methyl 1-tosyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate

A round bottom flask was charged with methyl1H-pyrrolo[3,2-c]pyridine-7-carboxylate (14 g, 79 mmol) and THF (225 mL)[Pharmablock] and the solution was cooled to about 5° C. followed by theaddition of KHMDS (1M in THF, 79 mL, 79 mmol). The solution was thenstirred for about 1 h followed by the addition of a solution of4-methylbenzene-1-sulfonyl chloride (15.2 g, 79.0 mmol) in THF (25 mL).The mixture was stirred for about 2 h at about 0 to 5° C. followed bythe addition of saturated aqueous NH₄Cl and DCM. The layers wereseparated and the organic solution was dried over MgSO₄, filtered,concentrated under reduced pressure and purified by silica gelchromatography (0-50% EtOAc/DCM) to give methyl1-tosyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (18.8 g, 72%): LC/MS(Table 1, Method as) R_(t)=2.10 min; MS m/z: 331 (M+H)⁺.

Step B: 7-(Methoxycarbonyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine 5-oxide

A round bottom flask was charged with methyl1-tosyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (16.0 g, 48.4 mmol) andEtOAc (150 mL). To the reaction solution was added a solution of3-chlorobenzoperoxoic acid (14.2 g, 82 mmol) in EtOAc (80 mL) andstirred at rt for about 16 h. To the reaction mixture was addedsaturated aqueous Na₂CO₃ (50 mL) and the layers were separated. Theaqueous layer was extracted with EtOAc (2×30 mL) and DCM (2×30 mL). Thecombined extracts were dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a thick oil that was dried on a vacuumpump to give 7-(methoxycarbonyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine5-oxide (11.6 g, 69%): LC/MS (Table 1, Method as) R_(t)=1.73 min; MSm/z: 347 (M+H)⁺.

Step C: Methyl 4-chloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate

A round bottom flask was charged with7-(methoxycarbonyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine 5-oxide (11.6 g,33.5 mmol) and PCl3 (26.5 mL, 285 mmol) and heated to about 60° C. forabout 2 h. The solution was cooled to rt and slowly poured into icewater with stirring and the resulting mixture was neutralized with theaddition of saturated aqueous Na₂CO₃. The aqueous mixture was extractedwith EtOAc (3×40 mL) and the combined extracts were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give methyl4-chloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (8.47 g, 69%):LC/MS (Table 1, Method as) R_(t)=2.46 min; MS m/z: 365 (M+H)⁺.

Preparation #46:7-Chloro-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridine-4-carboxamide

Step A: (E)-Ethyl 3-(2-bromothiazol-4-yl)acrylate

A 1 L round-bottom flask was charged with ethyl2-(triphenylphosphoranylidene)acetate (37.2 g, 107 mmol) in DCM (130 mL)to give a colorless solution. The solution was cooled to about 0° C. anda solution of 2-bromothiazole-4-carbaldehyde (20.5 g, 107 mmol)[ArkPharm] in DCM (500 mL) was added drop wise via a dropping funnel.The reaction mixture was slowly warmed to rt and stirred for about 2 hthen concentrated under reduced pressure. The mixture was taken up inEt₂O (300 mL) and stirred at about 40° C. for about 30 min. It was thencooled, filtered and washed with Et₂O (50 mL). The precipitate wasdiscarded and the filtrate was concentrated to half the volume. Theprecipitate formed was collected via filtration to give the first batchof product. The filtrate was concentrated and Et₂O was added (60 mL),the mixture was stirred at rt for about 20 min and the newly formedprecipitate was filtered again to collect a second batch of product. Thefiltrate from this batch was concentrated under reduced pressure andpurified silica gel chromatography (0-10% EtOAc/heptane). The materialthus obtained was recrystallized from Et₂O to give a third and finalbatch of product. All the batches were combined to give whitecrystalline material, (E)-ethyl 3-(2-bromothiazol-4-yl)acrylate (20.1 g,72%): LC/MS (Table 1, Method as) R_(t)=2.26 min; MS m/z: 262, 264(M+H)⁺.

Step B: (E)-Ethyl 3-(2-(1-methyl-1H-pyrazol-3-yl)thiazol-4-yl)acrylate

A 500 mL round bottom flask was charged with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(20.7 g, 100 mmol), (E)-ethyl 3-(2-bromothiazol-4-yl)acrylate (20.1 g,77.0 mmol), Na₂CO₃ (24.4 g, 230 mmol), PdCl₂(dppf) (5.61 g, 7.67 mmol)and (E)-ethyl 3-(2-bromothiazol-4-yl)acrylate (20.1 g, 77.0 mmol). Tothe solid mixture was added THF (150 mL): MeOH (21.00 mL): water (21 mL)and the suspension was degassed and purged with N₂ for about 20 min. Thereaction mixture was heated at about 75° C. for about 15 h. The reactionwas filtered and washed with EtOAc (100 mL) and the filtrate was washedwith water (70 mL). The aqueous layer was extracted with EtOAc (2×70 mL)and the combined organics were dried over MgSO₄, filtered andconcentrated. To the residue was added DCM (50 mL) and heptane (150 mL).The entire suspension was filtered, washed with acetone and isopropanoland dried in a vacuum oven to give the first batch of product. Thefiltrate was concentrated, dissolved in DCM (40 mL) and passed through asilica gel plug (eluent: 50% EtOAc/heptane). The filtrate wasconcentrated and refluxed in acetone (35 mL) and cooled. The precipitatewas filtered, washed with isopropanol, combined with the first batch anddried in a vacuum oven at about 70° C. for about 16 h to give (E)-ethyl3-(2-(1-methyl-1H-pyrazol-3-yl)thiazol-4-yl)acrylate (15.2 g, 75%):LC/MS (Table 1, Method as) R_(t)=1.94 min; MS m/z: 264 (M+H)⁺.

Step C: (E)-3-(2-(1-Methyl-1H-pyrazol-4-yl)thiazol-4-yl)acrylic acid

In a 20 mL reaction vial, (E)-ethyl3-(2-(1-methyl-1H-pyrazol-4-yl)thiazol-4-yl)acrylate (15.2 g, 57.7 mmol)and LiOH (4.15 g, 173 mmol) in MeOH (60 mL): water (12 mL) were added.The reaction mixture was stirred at about 40° C. for about 2 h. Thereaction mixture was concentrated, diluted with water (50 mL) and washedwith DCM (50×3 mL). The aqueous layer was acidified with 1N HCl until nomore precipitate formed. The precipitate was collected via filtrationand dried in a vacuum oven at about 60° C. for about 16 h to give(E)-3-(2-(1-methyl-1H-pyrazol-4-yl)thiazol-4-yl)acrylic acid (12.3 g,91%): ¹H NMR (400 MHz, DMSO-d₆) δ 12.42 (s, 1H), 8.38 (s, 1H), 7.94 (s,2H), 7.56 (s, 1H), 6.56 (s, 1H), 3.90 (s, 3H).

Step D: (E)-3-(2-(1-Methyl-1H-pyrazol-4-yl)thiazol-4-yl)acryloyl azide

To a suspension of(E)-3-(2-(1-methyl-1H-pyrazol-4-yl)thiazol-4-yl)acrylic acid (11.2 g,47.4 mmol) in acetone (170 mL) was added TEA (6.61 mL, 47.4 mmol) andthe mixture was cooled in an ice bath. Isobutyl chloroformate (6.22 mL,47.4 mmol) was added drop wise. After about 3.5 h a solution of NaN₃(3.85 g, 59.2 mmol) in water (15 mL) was added carefully and thereaction was stirred for about 3 h at about 0° C. The reaction mixturewas poured over ice and stirred for about 5 min, filtered and washedwith water (50 mL). The precipitate was dried in a vacuum oven at about60° C. for about 16 h to give(E)-3-(2-(1-methyl-1H-pyrazol-4-yl)thiazol-4-yl)acryloyl azide (9.6 g,78%): LC/MS (Table 1, Method as) R_(t)=1.91 min; MS m/z: 261 (M+H)⁺.

Step E: 2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridin-4(5H)-one

A 250 mL 3-neck round-bottomed flask was charged with tributylamine(6.10 mL, 25.6 mmol) in diphenylether (30 mL). The reaction mixture washeated to about 190° C. and a solution of(E)-3-(2-(1-methyl-1H-pyrazol-4-yl)thiazol-4-yl)acryloyl azide (5.60 g,21.5 mmol) in diphenylether (80 mL) was added carefully and the reactionwas stirred for about 5 h at about 190° C. The reaction mixture wascooled and poured onto petroleum ether (300 mL) and stirred for about 5min and filtered. The precipitate was dried in a vacuum oven at about70° C. for about 30 min. The material was suspended in Et₂O (100 mL) andheated at about 50° C. for about 20 min. It was then filtered and washedwith cold Et₂O. The precipitate was dried in a vacuum oven at about 70°C. for about 10 h to give2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridin-4(5H)-one (3.8 g,76%): LC/MS (Table 1, Method as) R_(t)=1.13 min; MS m/z: 233 (M+H)⁺.

Step F:7-Chloro-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridin-4(5H)-one

In a 250 mL round-bottom flask2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridin-4(5H)-one (3.7 g, 16mmol) in MeCN (80 mL) was added to give a suspension. The reactionmixture was heated with stirring to about 80° C. A solution of NCS (3.19g, 23.9 mmol)) in MeCN (25 mL) was added drop wise via a droppingfunnel, and the reaction was stirred for about 5 h at about 80° C. Themixture was diluted with water (100 mL), filtered and washed with water(40 mL). The precipitate was dried in a vacuum oven at about 70° C. forabout 16 h to give7-chloro-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridin-4(5H)-one(3.55 g, 84%): LC/MS (Table 1, Method as) R_(t)=1.27 min; MS m/z: 267(M+H)⁺.

Step G:4-Bromo-7-chloro-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridine

In a 100 mL 3-neck round-bottom flask a mixture of7-chloro-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridin-4(5H)-one(1.30 g, 4.87 mmol) and POBr₃ (3.91 g, 13.6 mmol) was heated to about70° C. for about 10 min then heated to to about 120° C. for about 45min. Additional POBr₃ (1.40 g, 4.87 mmol) was added and heated for about50 min. The mixture was cooled on an ice bath and to it was addedcarefully a mixture of crushed ice and water (40 mL). The mixture wasstirred at rt for about 16 h. To the suspension was added DCM (60 mL)and stirred for about 30 min, then filtered to remove some black solids.The DCM layer was separated and aqueous layer was extracted with DCM(2×20 mL). The combined organic layers were dried over MgSO₄, filteredand adsorbed on silica gel (4-6 g). The material was purified by silicagel chromatography (1-3% EtOAc/heptane) to give4-bromo-7-chloro-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridine(0.85 g, 53%): LC/MS (Table 1, Method as) R_(t)=2.20 min; MS m/z: 331(M+H)⁺.

StepH:7-Chloro-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridine-4-carbonitrile

In a 50 mL round-bottom flask,4-bromo-7-chloro-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridine(0.770 g, 2.13 mmol), Zn (CN)₂ (0.168 g, 1.44 mmol) and Pd(PPh₃)₄ (0.174g, 0.151 mmol) in DMF (10 mL) were added. The flask was degassed andpurged with nitrogen then heated thermally under nitrogen at about 110°C. to 120° C. for about 50 min. The reaction mixture was diluted withwater (25 mL) and stirred for about 5 min, filtered and washed withwater (6 mL). The precipitate was dried in a vacuum oven at about 70° C.for about 16 h to give crude7-chloro-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridine-4-carbonitrile(0.67 g, 98%). To a flask charged with NaOH (1M aqueous solution, 7.29mL, 7.29 mmol) in MeOH (12 mL) was added H₂O₂ (30% aqueous solution,1.24 mL, 12.2 mmol). This solution was added to a flask containing7-chloro-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridine-4-carbonitrile(0.670 g, 2.43 mmol) and stirred at about 30° C. for about 5 min. Thereaction mixture was diluted with water (51 mL) and stirred at rt forabout 5 min and filtered. The precipitate was triturated with Et₂O,filtered and dried in a vacuum oven for about 16 h to give7-chloro-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridine-4-carboxamide(0.597 g, 84%): LC/MS (Table 1, Method as) R_(t)=1.58 min; MS m/z: 294(M+H)⁺.

Preparation #47: Methyl4-((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclopentyl)-1-tosyl-1H-indole-7-carboxylate

Step A: Methyl4-(3-oxocyclopent-1-en-1-yl)-1-tosyl-1H-indole-7-carboxylate

A flask was charged with methyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole-7-carboxylate(1.74 g, 3.82 mmol, prepared using A from Preparation #1, step C withbis(pinacolato)diboron) in 2-methyl-THF(18.64 mL) and water (12.43 mL).The mixture was cooled to about 10° C. in a cold water bath. NaIO₄ (1.23g, 5.73 mmol) was added, the reaction was stirred for about 30 min andaqueous 1M HCl (8.41 mL, 8.41 mmol) was added drop wise. The mixture wasstirred at rt for about 16 h. Additional 2-methyl-THF (50 mL) was added,the aqueous layer was separated and the organic layer was washed with10% aqueous Na₂S₂O₃ (2×30 mL), saturated aqueous NaHCO₃ (30 mL) andbrine (20 mL). The organic layer was then dried over Na₂SO₄, filteredand concentrated to afford crude(7-(methoxycarbonyl)-1-tosyl-1H-indol-4-yl)boronic acid. In a 100 mLround-bottom flask the crude(7-(methoxycarbonyl)-1-tosyl-1H-indol-4-yl)boronic acid (1.59 g, 4.26mmol) in dioxane (17 mL) was added. A solution of Cs₂CO₃ (3.47 g, 10.7mmol) in water (4.26 mL) was added, the mixture was degassed withnitrogen followed by the addition of PdCl₂(PPh₃)₂ (0.209 g, 0.298 mmol)and 3-bromocyclopent-2-enone (1.4 mL, 12.8 mmol) under inert atmosphere.The mixture was heated at about 80° C. for about 3 h then cooled to rtand added DCM (100 mL) and water (50 mL). The layers were separated andthe aqueous layer was extracted with DCM (2×50 mL). The combinedorganics were dried over MgSO₄. The solvent was removed in vacuo and theresidue was purified using silica gel chromatography (0-60%EtOAc/heptane) to afford methyl4-(3-oxocyclopent-1-en-1-yl)-1-tosyl-1H-indole-7-carboxylate (1.2 g,69%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (d, J=3.9 Hz, 1H), 7.71 (d, J=7.9Hz, 1H), 7.67-7.62 (m, 2H), 7.58 (d, J=7.9 Hz, 1H), 7.39-7.31 (m, 2H),7.23 (d, J=3.9 Hz, 1H), 6.67 (t, J=1.8 Hz, 1H), 3.83 (s, 3H), 3.12 (dt,J=6.9, 1.9 Hz, 2H), 2.47 (dd, J=4.9, 2.5 Hz, 2H), 2.33 (s, 3H).

Step B: (R)-methyl 4-(3-oxocyclopentyl)-1-tosyl-1H-indole-7-carboxylate

In a 40 mL reaction vial,(2S,5S)-5-benzyl-3-methyl-2-(5-methylfuran-2-yl)imidazolidin-4-one(0.190 g, 0.703 mmol) and methyl4-(3-oxocyclopent-1-en-1-yl)-1-tosyl-1H-indole-7-carboxylate (3.05 g,7.45 mmol) in THF (5.67 mL) were added. The mixture was cooled to about0° C. and degassed with nitrogen. Di-tert-butyl2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.05 g, 3.40 mmol)and trichloroacetic acid (0.071 mL, 0.70 mmol) were added under inertatmosphere. The reaction mixture was stirred at about 4° C. for about 16h. Additional di-tert-butyl2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.420 g, 1.36 mmol)was added, and reaction was stirred with cooling for about 72 h. Thecrude material was adsorbed onto silica gel and purified via silica gelchromatography (0-45% EtAOc/heptane) to afford (R)-methyl4-(3-oxocyclopentyl)-1-tosyl-1H-indole-7-carboxylate (1 g, 79%). ¹H NMR(400 MHz, CDCl₃-d) δ 7.67-7.58 (m, 2H), 7.58-7.45 (m, 2H), 7.23-7.10 (m,3H), 6.75 (d, J=4.2 Hz, 1H), 3.91 (s, 3H), 3.73 (tdd, J=10.1, 7.6, 6.0Hz, 1H), 2.73-2.61 (m, 1H), 2.51-2.24 (m, 7H), 2.16-1.98 (m, 1H).

Step C: Methyl4-((1R,3S)-3-hydroxycyclopentyl)-1-tosyl-1H-indole-7-carboxylate

In a 200 mL round-bottom flask, (R)-methyl4-(3-oxocyclopentyl)-1-tosyl-1H-indole-7-carboxylate (1.60 g, 3.89 mmol)in THF (32.4 mL) was added. The solution was cooled to about −78° C.L-Selectride (7.78 mL, 7.78 mmol) was added drop wise over about 20 minand the mixture was stirred for about 16 h. The reaction mixture wascooled on an ice bath, saturated aqueous NH₄Cl (60 mL) was added dropwise then EtOAc (100 mL) and water (20 mL) were added. The organic layerwas separated, washed with brine, dried over Na₂SO₄, filtered,concentrated and purified via silica gel chromatography (0-65%EtOAc/heptane). The residue obtained was purified using chiralchromatography (Table 2, Method 19) to give methyl4-((1R,3S)-3-hydroxycyclopentyl)-1-tosyl-1H-indole-7-carboxylate (0.36g, 22%): LC/MS (Table 1, Method a) R_(t)=2.21 min; MS m/z: 431 (M+H₂O)⁺.

Step D: Methyl4-((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclopentyl)-1-tosyl-1H-indole-7-carboxylate

In a 40 mL reaction vial, methyl4-((1R,3S)-3-hydroxycyclopentyl)-1-tosyl-1H-indole-7-carboxylate (0.35g, 0.85 mmol) and PPh₃ (0.266 g, 1.02 mmol) in THF (3.4 mL) were added.The solution was cooled to about 10° C., DIEA (0.148 mL, 0.846 mmol) wasadded followed by drop wise addition of DIAD (0.197 mL, 1.02 mmol) andthe reaction mixture was stirred for about 30 min. Diphenylphosphorazidate (0.219 mL, 1.02 mmol) was added drop wise and stirred atrt for about 3 h. A solution of PPh₃ (0.289 g, 1.10 mmol) in THF (0.6mL) was added drop wise and the mixture was stirred for about 18 h.Water (0.183 mL, 10.2 mmol) was added and the mixture was heated atabout 45° C. for about 72 h. To the reaction mixture was added DCM (10.7mL, 166 mmol) and a solution of potassium hydrogenphosphate (0.737 g,4.23 mmol) in water (2.14 mL, 119 mmol). A solution of di-tert-butyldicarbonate (0.393 mL, 1.69 mmol) in DCM (2.14 mL, 33.2 mmol) was addeddrop wise and stirred at rt for about 1 h. Brine (2 mL) was added, theorganic layer was separated and washed with brine (3 mL), dried overNa₂SO₄, filtered, concentrated and purified via silica gelchromatography (0-40% EtOAc/heptane) to afford methyl4-((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclopentyl)-1-tosyl-1H-indole-7-carboxylate(0.396 g, 59%): LC/MS (Table 1, Method a) R_(t)=2.72 min; MS m/z: 530(M+H₂O)⁺.

Preparation #48: tert-Butyl3-((7-carbamoyl-2-(5-(morpholinomethyl)pyridin-2-yl)-1H-indol-4-yl)(methyl)amino)azetidine-1-carboxylate

To a mixture of 4-((6-bromopyridin-3-yl)methyl)morpholine (0.300 g, 1.17mmol) in THF (5 mL) was added n-BuLi (1.17 mL, 2.92 mmol). The mixturewas stirred at about −78° C. for about 1 h, and thentributylchlorostannane (0.949 g, 2.92 mmol) was slowly added. Themixture was allowed to warm to rt over about 1 h, and a saturatedsolution of NH₄Cl was added. The mixture was extracted with EtOAc andthe combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to yield crude4-((6-(tributylstannyl)pyridin-3-yl)methyl)morpholine. A solutioncontaining the tert-butyl3-((7-carbamoyl-2-iodo-1H-indol-4-yl)(methyl)amino)azetidine-1-carboxylate(0.300 g, 0.638 mmol, preparation #40) in DMF (2 mL) was treated withLiCl (0.270 g, 6.38 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (0.156 g, 0.191mmol) and 4-((6-(tributylstannyl)pyridin-3-yl)methyl)morpholine (0.894g, 1.91 mmol). The mixture was heated at about 100° C. for about 16 h,cooled, filtered through Celite® and partitioned between EtOAc andwater. The organic phase was washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by silica gelchromatography (0-5% MeOH/DCM) to afford tert-butyl3-((7-carbamoyl-2-(5-(morpholinomethyl)pyridin-2-yl)-1H-indol-4-yl)(methyl)amino)azetidine-1-carboxylate(0.172 g, 11%): LCMS (Table 1, Method av) R_(t)=1.24 min; MS m/z: 521(M+H)⁺.

Preparation #49: tert-Butyl6-(7-carbamoyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate

To a solution of tert-butyl6-(7-cyano-1-tosyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate(0.973 g, 1.97 mmol, prepared using AG from tert-butyl6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate(Preparation #W.1) with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) andPreparation #AH.1) in EtOH (3.93 mL) at about 0° C. was added NaOH (1Naqueous solution, 7.87 mL, 7.87 mmol) followed by H₂O₂ (30% aqueoussolution, 1.12 mL, 9.84 mmol). After about 10 min the ice bath wasremoved. After about 1 h additional NaOH (1N aqueous solution, 7 mL, 7mmol) and H₂O₂ (30% aqueous solution, 1.00 mL, 8.82 mmol) and DCM (3 mL)were added. The reaction mixture was allowed to stir for about 1 h andconcentrated down to about 15 mL and diluted with water (10 mL) and DCM(20 mL). The suspension was filtered to remove any solids. The DCM layerwas separated, dried over MgSO₄, filtered, concentrated and purified viasilica gel chromatography to give tert-butyl6-(7-carbamoyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,3-dihydro-,4-oxazepine-4(7H)-carboxylate(0.138 g, 20%): LC/MS (Table 1, Method as) R_(t)=1.90 min; MS m/z: 359(M+H)⁺.

General Procedure A: Suzuki Reaction of an Aryl or Heteroaryl Halidewith an Aryl or Heteroaryl Boronic Acid or Boronate

To a mixture of an aryl halide (preferably 1 equiv), a boronic acid orboronate ester (1 to 2 equiv, preferably 1.1 equiv), and an inorganicbase (such as, KF, Na₂CO₃, K₂CO₃ or Cs₂CO₃, preferably Na₂CO₃ or Cs₂CO₃)(1.1 to 16 equiv, preferably 2 equiv) in a solvent (such as THF, DME,DMF, 1,4-dioxane, 1,4-dioxane/water, DME/water, 1,4-dioxane/water,toluene/EtOH/water, 1,4-dioxane/EtOH/water or THF/MeOH/water preferablyTHF/MeOH/water, 1,4-dioxane/water, DME/water or 1,4-dioxane/EtOH/water)is added a palladium catalyst (for example Pd(OAc)₂, Pd₂dba₃, Pd(PPh₃)₄,bis(acetato)triphenylphosphinepalladium(II), polymer-bound FibreCat™1032, SiliaCat DPP-Pd, PdCl₂(dppf),(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II), orPd(PPh₃)₂C₂; preferably PdCl₂(dppf),(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II), or SiliaCatDPP-Pd 0.01 to 0.20 equiv, preferably 0.1 equiv) and a ligand (forexample tricyclohexylphosphine, tri-tert-butyl-phosphine; preferablynone or tricyclohexylphosphine; 0.01-1.0 equiv, preferably 0.16 equiv)is added optionally. The mixture is heated at about 40 to 120° C.(preferably about 70-85° C.) for about 1 to 48 h (preferably about 24 h)thermally, or at about 100 to 200° C. (preferably about 120 to 150° C.)for about 5 to 60 min (preferably about 20 to 45 min) in a microwave(preferably 5 min ramp time, 300 Watts max power, 250 psi max pressure).The mixture is allowed to cool to rt and is worked up using one of thefollowing methods. Method 1. For reactions containing water, the mixturemay be diluted with an organic solvent (such as DCM or EtOAc). Thelayers are separated, the organic solution is optionally washed withwater and/or brine, dried over anhydrous MgSO₄ or Na₂SO₄, filtered, andthe solvent is removed under reduced pressure to give the desiredcompound. Method 2. The mixture is concentrated under reduced pressure.Method 3. The catalyst is removed by filtration and the filtrate isconcentrated under reduced pressure.

Illustration of General Procedure A

Preparation #A.1: 4-(3-Aminophenyl)-1H-indole-7-carboxamide

A vessel was charged with 4-bromo-1H-indole-7-carboxamide (2.08 g, 8.70mmol, Preparation #2),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.10 g, 9.57mmol), sodium carbonate (2.77 g, 26.1 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.637 g,0.870 mmol) and purged with nitrogen. A mixture of THF (71.4 mL), MeOH(10 mL), and water (10 mL) was added and the reaction was stirred atabout 70° C. for about 24 h. The mixture was filtered through Celite®,the solvent was removed under reduced pressure and the residue waspurified by column chromatograph on silica gel eluted with MeOH/DCM(0-10%) to provide a solid. The solid was triturated with ether toprovide 4-(3-aminophenyl)-1H-indole-7-carboxamide (1.37 g, 63): LC/MS(Table 1, Method f) R_(t)=0.76 min; MS m/z: 293 (M+MeCN+H)⁺.

TABLE A.1 Examples prepared fromN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (prepared using E from 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and acryloylchloride) using General Procedure A R_(t) min m/z Exam- (Table 1, ESI+Aryl Bromide Product ple # Method) (M + H)⁺ Btk IC₅₀ 4-bromo-2-(3,5-dimethylisoxazol-4-yl)- 1H-indole-7-carboxamide (prepared using A fromPreparation #1 and 3,5- dimethylisoxazole-4- boronic acid pinacol ester)

A.1.1 2.84 (d) 415 B 4-bromo-2-(1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-indole- 7-carboxamide (prepared using A fromPreparation #1 and 1-(2- tetrahydropyranl)-1H- pyrazole-5-boronic acidpinacol ester)

A.1.2 2.87 (p) 470 A 4-bromo-2-(3,5-dimethyl- 1H-pyrazol-4-yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 3,5-dimethylpyrazole-4- boronic acid, pinacol ester)

A.1.3 2.51 (d) 414 B 4-bromo-2-(1-isopropyl- 1H-pyrazol-4-yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 1-isopropyl-1H-pyrazole-4- boronic acid pinacol ester)

A.1.4 2.85 (d) 428 A 4-bromo-2-(1,3-dimethyl- 1H-pyrazol-4-yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 1,3-dimethyl-1H-pyrazole-4- boronic acid, pinacol ester)

A.1.5 2.66 (d) 414 A 4-bromo-2-(1-ethyl-1H- pyrazol-4-yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 1-ethyl-1H-pyrazole-4-boronic acid, pinacol ester)

A.1.6 2.74 (d) 414 A 4-bromo-2-(1-isobutyl- 1H-pyrazol-4-yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 1-isobutyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-1H- pyrazole)

A.1.7 2.98 (d) 442 A 4-bromo-2-(1-(2- morpholinoethyl)-1H-pyrazol-4-yl)-1H-indole- 7-carboxamide (prepared using A fromPreparation #1 and 1-(2- morpholinoethyl)-1H - pyrazole-4-boronic acid,pinacol ester)

A.1.8 2.28 (d) 499 A 4-bromo-1H-indole-7 - carboxamide (Preparation #2)

A.1.9 1.31 (f) 320 B 4-bromo-2-(pyrimidin-5- yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and Pyrimidine-5-boronic acid pinacol ester)

A.1.10 2.56 (d) 398 A 4-bromo-2-(1-methyl-1H- pyrazol-5-yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester)

A.1.11 2.66 (d) 400 A 4-bromo-2-(pyridin-4-yl)- 1H-indole-7-carboxamide(prepared using A from Preparation #1 and 4- pyridineboronic acidpinacol ester)

A.1.12 2.22 (d) 397 A 4-bromo-2-(2- methoxypyridin-4-yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 2-methoxy-pyridine-4- boronicacid)

A.1.13 2.70 (d) 427 A 4-bromo-2-(3- cyanophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 3-cyanophenyl-boronic acid)

A.1.14 3.03 (d) 421 A 2-(3-acetamidophenyl)-4- bromo-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 3-acetamido-phenylboronic acid)

A.1.15 2.79 (d) 453 A 4-bromo-2-(6- fluoropyridin-3-yl)-1H-indole-7-carboxaimide (prepared using A from Preparation #1 and 2-fluoropyridine-5-boronic acid)

A.1.16 2.87 (d) 415 A 4-bromo-2-(2- fluoropyridin-3-yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 2-fluoropyridine-3-boronic acid)

A.1.17 2.86 (d) 415 A 4-bromo-2-(2- methoxypyridin-3-yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 2-methoxy-pyridine-3- boronic acid pinacol ester)

A.1.18 2.97 (d) 427 A methyl 3-(4-bromo-7- carbamoyl-1H-indol-2-yl)benzoate (prepared using A from Preparation #1 and 3-methoxy-carbonylphenylboronic acid)

A.1.19 2.77 (o) 454 A methyl 4-(4-bromo-7- carbamoyl-1H-indol-2-yl)benzoate (prepared using A from Preparation #1 and 4- methoxy-carbonylphenylboronic acid)

A.1.20 2.77 (o) 454 A 4-bromo-2-(2,3- dihydrobenzofuran-5-yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 2,3-dihydrobenzofuran-5- boronic acid)

A.1.21 2.75 (o) 438 A 4-bromo-2-(3- methoxyphenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 3-methoxy-phenylboronic acid)

A.1.22 2.78 (o) 426 A 4-bromo-2-(4- methoxyphenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 4-methoxy-phenylboronic acid)

A.1.23 2.76 (o) 426 A 4-bromo-2-(6- methylpyridin-3-yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 6-methylpyridine-3-boronic acid)

A.1.24 2.36 (d) 411 A 4-bromo-2-(3- carbamoylphenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 3- amino-carbonylphenylboronic acid)

A.1.25 2.68 (d) 439 A 4-bromo-2-(3- fluorophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 3-fluorophenylboronic acid)

A.1.26 2.82 (o) 414 A 4-bromo-2-(3- (dimethylamino)phenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 3-(N,N- dimethylamino) phenylboronic acid)

A.1.27 2.24 (o) 439 A 4-bromo-2-(2-methyl-5- (pyrrolidin-1-ylsulfonly)phenyl)-1H- indole-7-carboxamide (prepared using A fromPreparation #1 and 2- methyl-5-(pyrrolidin-1- ylsulfonyl)phenylboronicacid)

A.1.28 2.76 (o) 543 B 4-bromo-2-(2- fluorophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 2-fluorophenylboronic acid)

A.1.29 2.80 (o) 414 A 4-bromo-2-(6- morpholinopyridin-3-yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 6-(morpholin-4-yl)pyridine- 3-boronic acid pinacol ester)

A.1.30 2.64 (d) 482 A 4-bromo-2-(4-(4- methylpiperazine-1-carbonyl)phenyl)-1H- indole-7-carboxamide (prepared using A fromPreparation #1 and 3-(4- methyl-1- piperazinylcarbonyl) benzeneboronicacid pinacol ester)

A.1.31 2.34 (d) 522 A 4-bromo-2-(4- fluorophenyl)-1H-indole-7-carboxamidc (prepared using A from Preparation #1 and 4-fluorophenylboronic acid)

A.1.32 2.80 (o) 414 A 4-bromo-2-phenyl-1H- indole-7-carboxamide(prepared using A from Preparation #1 and phenylboronic acid pinacolester)

A.1.33 2.77 (o) 396 A 4-bromo-2-(2- (methylsulfonyl)phenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 2-(methylsulfonyl) phenylboronic acid)

A.1.34 2.85 (d) 474 B 4-bromo-2-(4- (dimethylcarbamoyl)phenyl)-1H-indole-7- carboxamide (prepared using A from Preparation #1and 4-(N,N- dimethylaminocarbonyl) phenylboronic acid)

A.1.35 2.76 (d) 467 A 4-bromo-2-(pyridin-3-yl)- 1H-indole-7-carboxamide(prepared using A from Preparation #1 and 3- pyridineboronic acidpinacol ester)

A.1.36 1.71 (a) 397 A 4-bromo-2-(4- (morpholine-4- carbonyl)phenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 4-(morpholine-4- carbonyl)phenylboronic acid pinacol ester)

A.1.37 2.74 (d) 509 A 4-bromo-2-(4- (pyrrolidine-1- carbonyl)phenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 4-(1-pyrrolidinylcarbonyl) benzeneboronic acid pinacol ester)

A.1.38 2.87 (d) 493 A 4-bromo-2-(4-(4- methylpiperazine-1-carbonyl)phenyl)-1H- indole-7-carboxamide (prepared using A fromPreparation #1 and 4-(4- methyl-1- piperazinylcarbonyl) benzeneboronicacid pinacol ester)

A.1.39 2.31 (d) 522 A 4-bromo-2-(4- (methylsulfonyl)phenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 4-(methylsulfonyl) phenylboronic acid)

A.1.40 2.49 (o) 474 A 4-bromo-2-(6- methoxypyridin-3-yl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and2-methoxy-5- pyridineboronic acid)

A.1.41 2.89 (d) 427 A 4-bromo-2-(4- cyanophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 4-cyanophenylboronic acid)

A.1.42 3.01 (d) 421 A 4-bromo-2-(2- methoxyphenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 2-methoxy-phenylboronic acid)

A.1.43 3.10 (d) 426 A 4-bromo-2-(4- (morpholinomethyl)phenyl)-1H-indole-7- carboxamide (prepared using A from Preparation #1and 4-(4- morpholinylmethyl)- benzeneboronic acid pinacol ester)

A.1.44 2.37 (d) 495 A 4-bromo-2-(4- carbamoylphenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #1 and 4-aminocarbonyl- phenylboronic acid)

A.1.45 2.61 (d) 439 A

TABLE A.2 Examples prepared fromN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazole-2-carboxamide (Preparation #4) using GeneralProcedure A R_(t) min (Table 1, m/z ESI+ Aryl Bromide Product Example #Method) (M + H)⁺ Btk IC₅₀ 4-bromo-2-(1-methy1-6-oxo-1,6-dihydropyridin-3- yl)-1H-indole-7- carboxamide (prepared using Afrom Preparation #1 and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridin-2(1H)-one (Preparation #5)

A.2.1 2.90 (d) 484 A 4-bromo-2-(1-methyl-1H- pyrazol-4-yl)-1H-indole-7-carboxamide (Preparation #10)

A.2.2 2.87 (d) 457 A

TABLE A.3 Examples prepared from2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-bromo-1H-indole-7-carboxamide (prepared using A with4-bromo-2-iodo-1H-indole-7-carboxamide (Preparation #1) and1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone [Combi-Blocks]) using General Procedure A R_(t) min(Table 1, m/z ESI+ Btk Boronate Product Example # Method) (M + H)⁺ IC₅₀3-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)quinazolin- 4(3H)-one [WO 2011159857]

A.3.1 1.89 (g) 518 A 6-fluoro-3-(2-methyl-3- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)quinazolin- 4(3H)-one [WO2011159857]

A.3.2 1.52 (g) 536 A 4-tert-butyl-N- (2-methyl-3- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)benzamide [WO 2006/099075]

A.3.3 1.84 (g) 549 A N-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)thiazole-2- carboxamide (Preparation #4)

A.3.4 1.51 (g) 500 A N-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl)- 4,5,6,7- tetrahydrobenzo [b]thiophene-2-carboxamide [WO 2006/099075]

A.3.5 1.76 (g) 553 A 4-cyclopropyl-N-(2-methyl- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)benzamide [US 20090105209]

A.3.6 1.68 (g) 533 A 4-(difluoromethyl)-N-(2- methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)benzamide (Preparation #29)

A.3.7 1.59 (g) 543 A 4-(2-cyanopropan- 2-yl)-N- (2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)benzamide (prepared using Dfrom 2- methyl-3-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)aniline[Combi-Block] and 4-(2- cyanopropan-2-yl)benzoic acid)

A.3.8 1.69 (g) 560 A

TABLE A.4 Examples prepared from4-bromo-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide (Preparation #18) using General Procedure AR_(t) min m/z (Table 1, ESI+ Btk Boronate Product Example # Method) (M +H)⁺ IC₅₀ N-(3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzyl)acrylamide (prepared using E from (3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)methanamine [ChemMaker] andacryloyl chloride)

A.4.1  1.59 (g) 479 A 2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

A.4.2  1.27 (f) 411 A N-(2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (prepared using E from 2- aminophenylboronic acidpinacol ester and acryloyl chloride)

A.4.3  1.62 (g) 465 A 2-((3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenoxy) methyl)thiazole (prepared using Q from 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) phenol and thiazol-2-ylmethanol)

A.4.4  1.83 (g) 509 A 2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [CombiBlocks]

A.4.5  1.15 (f) 425 A 2-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl)- 3,4-dihydroisoquinolin- 1(2H)-one(Preparation #3)

A.4.6  1.79 (f) 555 A phenylboronic acid

A.4.7  1.72 (f) 396 A 4-(3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenylamino) pyrimidine-2- carbonitrile (Preparation #6)

A.4.8  1.60 (f) 514 A (1s,4s)-4-hydroxy-N-(2- methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)-4- (trifluoromethyl)cyclohexane- carboxamide (Preparation #8)

A.4.9  1.56 (a) 619 A 4-(difluoromethyl)-N-(2- methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)benzamide (prepared using Dfrom 4- (difluoromethyl) benzoic acid [Oakwood] and 2-methyl-3-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl) aniline [Combi-Blocks])

A.4.10 2.06 (a) 579 A N-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)oxetan-3-amine (prepared using H from 2-methyl-3-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)aniline[Combi-Blocks] and 3- oxetanone [Molbridge])

A.4.11 1.84 (a) 481 A 4-(difluoromethyl)-N-(2- methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) phenyl)-N- (oxetan-3-yl)benzamide(Preparation #25)

A.4.12 1.94 (a) 635 A 2-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenylamino)ethanol (prepared using J from 2-methyl-3-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)aniline[Combi-Blocks] and 2-iodo- ethanol)

A.4.13 1.72 (a) 469 A 4-(difluoromethyl)-N-(2- hydroxyethyl)-N-(2-methyl-3- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)benzamide (prepared using J from 2- methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline [Combi-Blocks] and 2-iodo-ethanol, D from 4- (difluoromethyl) benzoic acid [Oakwood])

A.4.14 1.82 (a) 623 A N-(3-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (Preparation #22)

A.4.15 1.63 (g) 465 A 4-cyclopropyl- N-(2-methyl-3- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)benzamide [US 20090105209]

A.4.16 1.85 (g) 569 A N-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)thiazole-2- carboxamide (Preparation #4)

A.4.17 1.68 (g) 536 A 3-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl) quinazolin-4(3H)- one [WO 2011159857]

A.4.18 1.66 (g) 554 A 6-fluoro-3-(2-methyl-3- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl) quinazolin-4(3H)- one [WO2011159857]

A.4.19 1.71 (g) 572 A

TABLE A.5 Examples prepared from 4-bromo-1H-indole-7-carboxamide(Preparation #2) using General Procedure A R_(t) min m/z (Table 1, ESI+Boronate Product Example # Method) (M + H)⁺ Btk IC₅₀2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline

A.5.1 1.04 (f) 252 C N-(3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (Preparation #22)

A.5.2 1.36 (f) 306 B 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- arnine

A.5.3 0.45 (f) 253 C 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- amine [Maybridge]

A.5.4 0.31 (f) 253 C 3-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)quinazolin-4(3H)- one [US 20100160303]

A.5.5 1.82 (a) 395 B 4-(tert-butyl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)benzamide [WO2006/099075]

A.5.6 2.28 (a) 426 C

TABLE A.6 Examples prepared from4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole- 7-carboxamide(Preparation #P.1) using General Procedure A m/z R_(t) min ESI+ (Table1, (M + Me Arylbromide Product Example # Method) CN + H)⁺ Btk IC₅₀3-bromo-N- (cyanomethyl) benzenesulfonamide (Preparation #29)

A.6.1 1.32 (f) 396 C 3-bromo-N-methylaniline

A.6.2 0.95 (f) 307 C

TABLE A.7 Examples prepared from4-iodo-2-(pyridin-3-yl)-1H-indole-7-carboxamide (Example #F.1) usingGeneral Procedure A R_(t) min m/z (Table 1, APCI+ Boronate ProductExample # Method) (M + H)⁺ Btk IC₅₀ 4-(tert-butyl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)benzamide [WO2006/099075]

A.7.1 1.93 (aa) 503 A 3-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)quinazolin-4(3H)- one [WO 2011159857]

A.7.2 1.88 (ac) 472 A N-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide [WO 2006/099075]

A.7.3 1.85 (ab) 507 A 2-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)isoindolin-1-one [U.S. 20100160303]

A.7.4 1.90 (ac) 459 A 6-methyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)isoindolin-1-one[U.S. 2010/0160303]

A.7.5 1.99 (ac) 473 A 6-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)isoindolin-1-one[WO 2011/159857 A1]

A.7.6 1.98 (a) 477 A N-(4-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)thiazole-2- carboxamide (prepared using E from5-amino-2- methylphenylboronic acid, pinacol ester and1,3-thiazole-2-carbonyl chloride [Maybridge-International])

A.7.7 1.65 (f) 454 C N-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)thiazole-2- carboxamide (Preparation #4)

A.7.8 1.87 (a) 454 A

TABLE A.8 Examples prepared from4-iodo-2-(p-tolyl)-1H-indole-7-carboxamide (prepared using F from1-(p-tolyl)ethanone) using General Procedure A R_(t) min m/z (Table 1,APCI+ Btk Boronic Acid or Boronate Product Example # Method) (M + H)⁺IC₅₀ pyrazole-3-boronic acid

A.8.1 1.93 (a) 317 B 3,5-dimethylisoxazole-4- boronic acid pinacol ester

A.8.2 2.27 (a) 346 B pyridine-3-boronic acid

A.8.3 2.15 (a) 328 B pyridine-4-boronic acid

A.8.4 2.27 (a) 328 B 5-acetylthiophen-2-ylboronic acid

A.8.5 0.92 (e) 375 B 4,4,5,5-tetramethyl-2- (thiophen-3-yl)-1,3,2-dioxaborolane

A.8.6 0.97 (e) 333 B 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole

A.8.7 0.83 (e) 331 B 1H-pyrazol-3-ylboronic acid

A.8.8 0.81 (e) 317 B thiophen-2-ylboronic acid

A.8.9 0.97 (e) 333 B thiophen-3-ylboronic acid

 A.8.10 0.97 (e) 333 B

TABLE A.9 Examples prepared from4-iodo-2-(p-tolyl)-1H-indole-7-carboxamide (prepared with F using1-(4-fluorophenyl)ethanone) using General Procedure A R_(t) min m/z(Table 1, APCI+ Btk Boronic Acid or Boronate Product Example # Method)(M + H)⁺ IC₅₀ pyrimidine-5-boronic acid

A.9.1 1.82 (a) 333 B pyridine-3-boronic acid

A.9.2 2.05 (a) 332 A 3,5-dimethylisoxazole-4- boronic acid pinacol ester

A.9.3 2.18 (a) 350 B pyridine-4-boronic acid

A.9.4 2.15 (a) 332 B pyrazole-3-boronic acid

A.9.5 1.87 (a) 321 B 6-fluoro-2-(2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)isoindolin-1-one [WO 2011/159857]

A.9.6 2.37 (a) 494 A N-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide [WO 2006/099075]

A.9.7 2.66 (a) 524 C

TABLE A.10 Examples prepared from4-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7- carboxamide (preparedusing A from 4-bromo-2-iodo-1H-indole-7-carboxamide (Preparation #1)with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)using General Procedure A R_(t) min m/z (Table 1, APCI+ Btk BoronateProduct Example # Method) (M + H)⁺ IC₅₀ 3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)quinazolin-4(3H)- one [WO2011159857]

A.10.1 2.11 (c) 475 A 6-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)quinazolin-4(3H)-one [US 2010/0160303]

A.10.2 1.90 (a) 493 A N-(3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H- indol-4-yl)-2-methylphenyl)-N-(oxetan-3-yl)thiazole-2- carboxamide (prepared using H from 2-methyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)aniline[Combi-Blocks] and 3-oxetanone [Molbridge]), E with thiazole- 2-carbonylchloride [Maybridge])

A.10.3 1.48 (g) 513 A N-methyl-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)thiazole-2-carboxamide (Preparation #19)

A.10.4 1.52 (f) 471 B N-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide [WO 2006/099075]

A.10.5 1.84 (g) 510 A

TABLE A.11 Examples prepared from4-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-7- carboxamide (preparedusing A from 4-bromo-2-iodo-1H-indole-7-carboxamide (Preparation #1) and2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane)using General Procedure A R_(t) min (Table 1, m/z ESI+ Btk BoronateProduct Example # Method) (M + H)⁺ IC₅₀ 3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)quinazolin-4(3H)- one [WO2011159857]

A.11.1 1.51 (g) 477 A 6-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)quinazolin-4(3H)-one [WO 2011159857]

A.11.2 1.55 (g) 495 A

TABLE A.12 Examples prepared from4-bromo-2-(4-fluorophenyl)-1H-indole-7-carboxamide (prepared using Afrom 4-bromo-2-iodo-1H-indole-7-carboxamide (Preparation #1) and 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) using GeneralProecedure A R_(t) min (Table 1, m/z ESI+ Btk Boronate Product Example #Method) (M + H)⁺ IC₅₀ 3-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)quinazolin- 4(3H)-one [WO 2011159857]

A.12.1 1.78 (g) 489 A

TABLE A.13 Examples prepared from4-bromo-2-(pyrimidin-5-yl)-1H-indole-7-carboxamide (prepared using Afrom 4-bromo-2-iodo-1H-indole-7-carboxamide (Preparation #1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine) using GeneralProcedure A R_(t) min (Table 1, m/z ESI+ Btk Boronate Product Example #Method) (M + H)⁺ IC₅₀ 3-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)quinazolin-4(3H)- one [WO 2011159857]

A.13.1 1.52 (g) 473 B 6-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)quinazolin-4(3H)-one [WO 2011159857]

A.13.2 1.59 (g) 491 B 4-(difluoromethyl)-N-(2- methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl)benzamide (Preparation #29)

A.13.3 1.64 (g) 498 B 4-cyclopropyl-N-(2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)benzamide (prepared using B with 2-methyl-3-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)aniline and4-(2-cyanopropan-2- yl)benzoic acid)

A.13.4 1.73 (g) 488 B

TABLE A.14 Examples prepared from4-bromo-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-1H-indole-7-carboxamide (prepared using A from4-bromo-2-iodo-1H-indole-7-carboxamide (Preparation #1) and2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (Preparation #26) using General Procedure A R_(t) min(Table 1, m/z ESI+ Btk Boronate Product Example # Method) (M + H)⁺ IC₅₀6-fluoro-3-(2-methyl-3- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)quinazolin- 4(3H)-one [WO 2011159857]

A.14.1 1.65 (g) 551 A

TABLE A.15 Examples prepared from2-(3-chloro-2-(hydroxymethyl)phenyl)-6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one [U.S. 20100222325] using General Procedure AR_(t) min (Table 1, m/z ESI+ Btk Boronate Product Example # Method) (M +H)⁺ IC₅₀ 2-(1-methyl-1H-pyrazol-4- yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indole-7-carboxamide (prepared using A fromPreparation #1 with 1- methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole, and P with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2- dioxaborolane))

A.15.1 2.77 (o) 548 A

General Procedure B: Nucleophilic Displacement of an Aryl Halide with anAmine

To a solution of an aryl halide or heteraryl halide and an appropriateorganic solvent (such as DMSO, 1,4-dioxane, n-butanol, THF, pyridine,preferably DMSO or pyridine) was added an amine (1 to 10 equiv,preferably 1equiv) and abase (such as TEA, pyridine, DIEA, K₂CO₃,preferably TEA; 1 to 5 equiv, preferably 1equiv.). The resultingsolution is stirred at about 20 to 150° C. (preferably about 130-150°C.) thermally for a period of about 1 h to 72 h (preferably about 24 h)or in a microwave for about 5 min to 2 h (preferably about 30 mi). Themixture is optionally concentrated in vacuo or under a warm nitrogenstream to give the intermediates or targeted compound or optionallyfiltered through a media (such as SiCO₃ or Celite®) which is rinsed withan appropriate solvent (such as EtOAc, 1,4-dioxane, THF, MeCN, DCM,Et₂O, MeOH, EtOH, DMSO, 1:1 MeOH/DMSO, 2:1 MeOH/DMSO) and thenoptionally concentrated in vacuo or under a warm nitrogen stream to givethe targeted compound.

Illustration of General Procedure B Preparation #B.1: (R)-tert-Butyl1-(7-cyano-1H-in dol-4-yl)piperidin-3-ylcarbamate

A mixture of (R)-tert-butyl piperidin-3-ylcarbamate (1.501 g, 7.49 mmol)and 4-fluoro-1H-indole-7-carbonitrile (0.6 g, 3.75 mmol) in pyridine(3.02 mL, 37.5 mmol) were heated at about 150° C. for about 30 min in amicrowave oven. The mixture was evaporated to dryness and the resultingresidue was purified by silica gel chromatography eluting with agradient 30 to 100% of EtOAc in hexanes to give (R)-tert-butyl1-(7-cyano-1H-indol-4-yl)piperidin-3-ylcarbamate (0.4 g, 31%); LC/MS(Table 1, Method g) R_(t)=1.69 min.; MS m/z: 341 (M+H)⁺

General Procedure C: Hydrolysis of an Ester to a Carboxylic Acid

To a flask containing an ester (preferably 1 equiv) either neat or in anorganic solvent (such as 1,4-dioxane, MeOH, or THF/MeOH, preferably1,4-dioxane) is added an aqueous base (such as aqueous NaOH or LiOH;1-10 equiv, preferably 2-6 equiv). The mixture is stirred at about 0 to100° C. (preferably about 25 to 60° C.) for about 1 to 48 h (preferablyabout 4 to 24 h). The organic solvent is optionally be concentrated invacuo. The mixture is then acidified by the addition of a suitableaqueous acid (such as aqueous HCl). If a precipitate forms, it may becollected via filtration to give product. The mixture or the filtrate ifthe solid is not product may optionally be concentrated in vacuo to givethe target compound as a carboxylate salt. Alternatively, the mixture isoptionally filtered through a media (such as silica gel or Celite®)which is rinsed with an appropriate solvent (such as EtOAc, 1,4-dioxane,THF, MeCN, DCM, Et₂O, MeOH, EtOH) and then optionally concentrated invacuo to give a residue as the target compound. Either the residue orthe solution may be optionally partitioned between water and an organicsolvent (such as EtOAc, Et₂O or DCM). The organic layer is isolated andmay optionally be washed in no particular order with water and/oraqueous solutions containing an acid (such as HCl, AcOH or NH₄Cl) and/oraqueous solutions containing a base (such as NaHCO₃, Na₂CO₃, NaOH, KOHor NH₄OH) and/or aqueous solutions containing an inorganic salt (such asNaCl, Na₂SO₃ or Na₂S₂O₃). The organic solution may then be optionallydried with a drying agent (such as anhydrous MgSO₄ or Na₂SO₄), filteredand concentrated in vacuo to give the target compound.

Illustration of General Procedure C Example #C.1:(E)-4-((3-(7-Carbamoyl-1H-indol-4-yl)phenyl)amino)-4-oxobut-2-enoic acid

(E)-Methyl4-((3-(7-carbamoyl-1H-indol-4-yl)phenyl)amino)-4-oxobut-2-enoate (0.610g, 1.68 mmol, Example #D.1) was suspended in 1,4-dioxane (8.39 mL).Lithium hydroxide (1M in water, 8.39 mL, 8.39 mmol) was added and themixture was stirred at about 60° C. for about 1 h. The reaction wasconcentrated to about 8 mL and diluted with water (10 mL). The pH wasadjusted to about 4 using 1N HCl. The solids were collected, washed withwater, and dried under vacuum to provide(E)-4-((3-(7-carbamoyl-1H-indol-4-yl)phenyl)amino)-4-oxobut-2-enoic acid(0.45 g, 77%) as a solid. 50 mg of the crude product was furtherpurified by preparative-HPLC (Table 1, Method af) to afford 30.9 mg toprovide analytically pure(E)-4-((3-(7-carbamoyl-1H-indol-4-yl)phenyl)amino)-4-oxobut-2-enoicacid: LC/MS (Table 1, Method f) R_(t)=1.64 min; MS m/z: 350 (M+H)⁺ (BtkIC₅₀=C)

General Procedure D: Formation of an Amide from an Amine and aCarboxylic Acid

To a flask is added in no particular order, a carboxylic acid orcarboxylate salt (1 to 5 equiv, preferably 1.1 to 1.5 equiv), an amine(1 to 5 equiv, preferably 1 to 1.5 equiv), an organic solvent (such asDCM, DCE, THF, or 1,4-dioxane, DMF, DMF/pyridine preferably DCM orDMF/pyridine), a peptide coupling reagent (such as BOP-Cl, HATU, EDC,DCI, PyBOP, or EDC.HCl, preferably HATU or EDC; 1 to 10 equiv,preferably 1 to 2.5 equiv), a base (such as TEA, DIEA, pyridine or DIEA,preferably DIEA; 1 to 20 equiv, preferably 1 to 5 equiv) and optionallyHOBt (0 to 5 equiv, preferably 0 to 1 equiv). The mixture is thenstirred at about 10 to 60° C. (preferably about 25 to 50° C.) for about5 min to 48 h (preferably about 5 min to 24 h). Optionally, additionalamounts of the reagents above can be added to drive the reaction tocompletion. The mixture is optionally concentrated in vacuo to give thetargeted compound. The mixture is optionally filtered through a media(such as silica gel or Celite®) which is rinsed with an appropriatesolvent (such as EtOAc, 1,4-dioxane, THF, MeCN, DCM, Et₂O, MeOH, EtOH)and then optionally concentrated in vacuo to give a residue. Either theresidue or the solution may be optionally partitioned between water andan organic solvent (such as EtOAc, Et₂O or DCM). If the product does notpartition, the mixture may be stirred for 5 min to 1 h (preferably 30min) and the solid may be collected via vacuum filtration.Alternatively, the organic layer is isolated and may be optionallywashed in no particular order with water and/or aqueous solutionscontaining an acid (such as HCl, AcOH or NH₄Cl) and/or aqueous solutionscontaining a base (such as NaHCO₃, Na₂CO₃, NaOH, KOH or NH₄OH) and/oraqueous solutions containing an inorganic salt (such as NaCl, Na₂SO₃ orNa₂S₂O₃). The organic solution may then be optionally dried with adrying agent (such as anhydrous MgSO₄ or Na₂SO₄), filtered andconcentrated in vacuo to give the targeted compound.

Illustration of General Procedure D Example #D.1: (E)-Methyl4-((3-(7-carbamoyl-1H-indol-4-yl)phenyl)amino)-4-oxobut-2-enoate

To a solution of (E)-4-methoxy-4-oxobut-2-enoic acid (0.43 g, 3.28 mmol)in DCM (40 mL) and DIEA (0.59 mL, 3.58 mmol) was added HATU (1.362 g,3.58 mmol). The mixture was stirred at rt for 5 min then4-(3-aminophenyl)-1H-indole-7-carboxamide (0.75 g, 2.98 mmol,Preparation #A.1) was added. The mixture was stirred at rt for about 3h. The mixture was concentrated and the residue was suspended betweenwater and EtOAc. The mixture was stirred at rt for about 30 min,filtered to collect the solid, which was washed with water and EtOAc,and dried under vacuum to provided (E)-methyl4-((3-(7-carbamoyl-1H-indol-4-yl)phenyl)amino)-4-oxobut-2-enoate (0.64g, 59%): LC/MS (Table 1, Method f) R_(t)=1.45 min; MS m/z: 364 (M+H)⁺(Btk IC₅₀=A)

TABLE D.1 Examples prepared fromN-(3-(2-(2-(aminomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide (Example #1) using GeneralProcedure D R_(t) min (Table 1, m/z ESI+ Acid Product Example # Method)(M + H)⁺ Btk IC₅₀ but-2-ynoic acid

D.1.1 3.13 (d) 548 C acrylic acid

D.1.2 3.10 (d) 536 C 2-cyanoacetic acid

D.1.3 3.05 (d) 549 B 3-(dimethyl- amino)ropanoic acid HCl

D.1.4 2.64 (d) 581 B 3-(piperidin-1- yl)propanoic acid

D.1.5 2.38 (o) 621 C 2-phenoxyacetic acid

D.1.6 3.06 (o) 616 C 2-(4-fluoro- phenoxy)acetic acid

D.1.7 3.08 (o) 634 C butyric acid

D.1.8 2.87 (o) 552 C (E)-but-2-enoic acid

D.1.9 2.84 (o) 550 C methacrylic acid

D.1.10 3.20 (d) 550 C propiolic acid

D.1.11 3.10 (d) 534 B

TABLE D.2 Examples prepared from an amine and2-(3-oxobenzo[d]isothiazol-2(3H)-yl)acetic acid [Matrix] using GeneralProcedure D R_(t) min (Table 1, m/z ESI+ Amine Product Example # Method)(M + H)⁺ Btk IC₅₀ 4-(2-aminophenyl)-1H- indole-7-carboxamide (preparedusing A from 4 -bromo-1H-indole-7- carboxamide (Preparation #2) and2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)aniline)

D.2.1 1.42 (f) 443 C

TABLE D.3 Examples prepared fromN-(3-(3-amino-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide (Preparation #7) using GeneralProcedure D R_(t) min (Table 1, m/z ESI+ Acid Product Example # Method)(M + H)⁺ Btk IC₅₀ 2-cyanoacetic acid

D.3.1 2.58 (d) 459 C acrylic acid

D.3.2 2.69 (d) 446 C (E)-but-2-enoic acid

D.3.3 2.82 (d) 460 C methacrylic acid

D.3.4 2.89 (d) 460 C but-2-ynoic acid

D.3.5 2.52 (d) 458 C 2-(4-fluorophenoxy)acetic acid

D.3.6 3.09 (d) 544 C

TABLE D.4 Examples prepared from an(E)-4-((3-(7-carbamoyl-1H-indol-4-yl)phenyl)amino)-4- oxobut-2-enoicacid (Example #C.1) using General Procedure D R_(t) min (Table 1, m/zESI+ Amine Product Example # Method) (M + H)⁺ Btk IC₅₀ Methylamine

D.4.1 1.60 (f) 363 C Dimethylamine

D.4.2 1.66 (f) 377 C ethanamine

D.4.3 1.68 (f) 377 C cyclopropanamine

D.4.4 1.70 (f) 389 C

TABLE D.5 Examples prepared from an acid and2-(1-acetylpiperidin-4-yl)-4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide (Example #L.1) using GeneralProcedure D R_(t) min (Table 1, m/z ESI+ Acid Product Example # Method)(M + H)⁺ Btk IC₅₀ 4-cyclopropylbenzoic acid [Astra tech]

D.5.1 1.77 (f) 535 B

TABLE D.6 Examples prepared from4-(3-aminophenyl)-1H-indole-7-carboxamide (Preparation #A.1) usingGeneral Procedure B R_(t) min (Table 1, m/z ESI+ Acid Product Example #Method) (M + H)⁺ Btk IC₅₀ 2- ((dimethylamino)methyl)a- crylic acid(prepared using J from 2- (bromomethyl)acrylic acid and dimethylaminehydrochloride)

D.6.1 2.24 (d) 363 A 2- ((dimethylamino)methyl)a- crylic acid (preparedusing J from 2- (bromomethyl)acrylic acid and morpholine)

D.6.2 2.27 (d) 405 A

TABLE D.7 Examples prepared from4-(3-amino-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide (Example #A.4.5) usingGeneral Procedure D. Example m/z ESI+ Btk Acid Product # R_(t) min (M +H)⁺ IC₅₀ (Z)-2-methylbut-2-enoic acid

D.7.1 0.73 (e) 507 A (E)-4-(dimethyl- amino)but-2-enoic acidhydrochloride

D.7.2 0.57 (e) 536 A 3-(piperidin-1- yl)propanoic acid

D.7.3 0.59 (e) 564 B 2-cyanoacetic acid

D.7.4 0.66 (e) 492 A methacrylic acid

D.7.5 0.71 (e) 493 A acrylic acid

D.7.6 0.68 (e) 479 A 2-chloro-2,2- difluoroacetic acid

D.7.7 0.77 (e) 537 A 2-chloropropanoic acid

D.7.8 0.72 (e) 515 A (E)-but-2-enoic acid

D.7.9 0.71 (e) 493 A (Z)-4-amino-4-oxobut-2- enoic acid

D.7.10 0.62 (e) 522 A 2-(4-fluoro- phenoxy)acetic acid

D.7.11 0.78 (e) 577 A 3-(pyrrolidin-1- yl)propanoic acid

D.7.12 0.58 (e) 550 A 2-(4-cyano- phenoxy)acetic acid

D.7.13 0.75 (e) 584 A 2-(pyridin-3-yloxy)acetic acid

D.7.14 0.58 (e) 560 A cyclopent-1- enecarboxylic acid

D.7.15 0.75 (e) 519 A (E)-2-methylpent-2- enoic acid

D.7.16 0.78 (e) 521 A (Z)-3-chloroacrylic acid

D.7.17 0.70 (e) 513 A (E)-4-methoxy-4-oxobut- 2-enoic acid

D.7.18 0.72 (e) 537 A cyclohex-1- enecarboxylic acid

D.7.19 0.78 (e) 533 A (E)-4-ethoxy-4-oxobut- 2-enoic acid

D.7.20 0.75 (e) 551 A 2-phenoxyacetic acid

D.7.21 0.79 (e) 559 A 2-fluoroacetic acid

D.7.22 0.66 (e) 485 A 3-(dimethyl- amino)propanoic acid

D.7.23 0.58 (h) 524 A 2-(pyridin-2- yloxy)acetic acid

D.7.24 0.69 (e) 560 A (E)-4-amino-4-oxobut- 2-enoic acid

D.7.25 0.59 (e) 522 A 2-chlorobutanoic acid

D.7.26 0.74 (e) 529 A 3-(4-methylpiperazin-1- yl)propanoic acid

D.7.27 0.52 (e) 579 A 2-(pyridazin-3- yloxy)acetic acid

D.7.28 0.61 (e) 561 A cyclohexanecarboxylic acid

D.7.29 1.75 (e) 535 A 2-methylthiazole-4- carboxylic acid

D.7.30 0.75 (ae) 550 A cyclopentanecarboxylic acid

D.7.31 0.75 (ae) 521 A 5-methylthiazole-2- carboxylic acid

D.7.32 0.77 (ae) 550 A tetrahydro-2H-pyran-4- carboxylic acid

D.7.33 0.65 (ae) 537 A 3- methoxycyclohexane- carboxylic acid

D.7.34 0.71 (ae) 565 A 3-methylbutanoic acid

D.7.35 0.73 (ae) 509 A 1-methylpiperidine-4- carboxylic acid

D.7.36 0.56 (ae) 550 A 1-methylpiperidine-3- carboxylic acid

D.7.37 0.57 (ae) 550 B isothiazole-4-carboxylic acid

D.7.38 0.67 (ae) 536 A nicotinic acid

D.7.39 0.59 (ae) 530 A isobutyric acid

D.7.40 0.69 (ae) 495 A propionic acid

D.7.41 0.67 (e) 481 A

TABLE D.8 Compounds made from4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide (Example #16) usingGeneral Procedure D. m/z ESI+ Acid Product Example # R_(t) min (M + H)⁺Btk IC₅₀ (E)-4-ethoxy-4-oxobut-2- enoic acid

D.8.1 0.69 (ae) 392 A (E)-3-(1-methyl-1H- pyrazol-4-yl)acrylic acid

D.8.2 0.62 (ae) 400 B (E)-3-(pyridin-2-yl)acrylic acid

D.8.3 0.55 (ae) 397 B (E)-3-(pyridin-3-yl)acrylic acid

D.8.4 0.53 (ae) 397 B (E)-3-(thiazol-2-yl)acrylic acid

D.8.5 0.65 (ae) 403 B (E)-3-cyclopropylacrylic acid

D.8.6 0.69 (ae) 360 B 2-phenylacrylic acid

D.8.7 0.75 (ae) 396 B (E)-4-methylpent-2-enoic acid

D.8.8 0.74 (ae) 362 B (E)-but-2-enoic acid

D.8.9 0.64 (ae) 334 B methacrylic acid

D.8.10 0.65 (ae) 334 C 2-methylenebutanoic acid

D.8.11 0.69 (ae) 348 C acetic acid

D.8.12 0.56 (ae) 308 C 3-morpholinopropanoic acid

D.8.13 0.50 (ae) 407 C 3-(pyrrolidin-1- yl)propanoic acid

D.8.14 0.51 (ae) 391 C (Z)-4-(ethylamino)-4- oxobut-2-enoic acid

D.8.15 0.62 (ae) 391 A

TABLE D.9 Examples prepared from(Z)-4-((3-(7-carbamoyl-1H-indol-4-yl)phenyl)amino)-4- oxobut-2-enoicacid (Preparation #14) using General Procedure D R_(t) min (Table 1, m/zESI+ Amine Product Example # Method) (M + H)⁺ Btk IC₅₀2-methoxyethylamine

D.9.1 1.42 (g) 407 B Ethanamine

D.9.2 1.41 (g) 377 A

TABLE D.10 Examples prepared from propiolic acid with an amine usingGeneral Procedure D R_(t) min (Table 1, m/z ESI+ Amine Product Example #Method) (M + H)⁺ Btk IC₅₀ 4-(Azetidin-3- yl(methyl)amino)-2-methyl-1H-indole-7- carboxamide hydrochloride (Prepared using A fromPreparation #40 with methylboronic acid and G with HCl)

D.10.1 1.35 (at) 311 A

General Procedure E: Formation of an Amide from an Amine and an AcidHalide or Anhydride

To a solution of an amine (1 to 3 equiv, preferably 1 to 3 equiv),optionally as a hydrochloride salt, in an organic solvent (such as DCM,DCE, DMF, DMA, NMP, THF, Et₂O or 1,4-dioxane, preferably DMF, DMA, orDCM) is added a base (such as TEA, DIEA or pyridine; 1 to 4 equiv,preferably TEA or DIEA 1 to 3 equiv) and an acid halide or anhydride (1to 4 equiv, preferably 1 to 4 equiv). The mixture is optionally cooledto about 0° C. prior to addition of an acid halide or anhydride. Themixture is allowed to stir at about 0 to 60° C. (preferably about 0 to50° C.) for about 5 min to 20 h (preferably about 20 min to 2 h). Themixture is optionally neutralized with AcOH. The mixture is optionallyconcentrated in vacuo to give the final compound. The mixture isoptionally filtered through a media (such as silica gel or Celite®)which is rinsed with an appropriate solvent (such as EtOAc, 1,4-dioxane,THF, MeCN, DCM, Et₂O, MeOH, EtOH) and then optionally concentrated invacuo to give a residue. Either the residue or the solution may beoptionally partitioned between water and an organic solvent (such asEtOAc, Et₂O or DCM). The organic layer is isolated and may be optionallywashed in no particular order with water and/or aqueous solutionscontaining an acid (such as HCl, AcOH or NH₄Cl) and/or aqueous solutionscontaining a base (such as NaHCO₃, Na₂CO₃, NaOH, KOH or NH₄OH) and/oraqueous solutions containing an inorganic salt (such as NaCl Na₂SO₃ orNa₂S₂O₃). The organic solution may then be optionally dried with adrying agent (such as anhydrous MgSO₄ or Na₂SO₄), filtered andconcentrated in vacuo to give the targeted compound. Alternatively, theresidue from concentration of the reaction is suspended in water,sonicated, and collected via vacuum filtration.

Illustration of General Procedure E Example #E.1.4-(3-Acrylamido-2-methylphenyl)-2-(4,4-difluorocyclohex-1-en-1-yl)-1H-indole-7-carboxamide

To a vial was added4-(3-amino-2-methylphenyl)-2-(4,4-difluorocyclohex-1-en-1-yl)-1H-indole-7-carboxamide(0.189 g, 0.496 mmol, Example #21) in DCM (5 mL), and DIEA (0.129 mL,0.743 mmol). The mixture was cooled to about 0° C. and acryloyl chloride(0.044 mL, 0.545 mmol) was added while stirring. The mixture was warmedto rt over about 20 min, then concentrated and the residue was suspendedin water (30 mL). The suspension was sonicated for about 5 min,filtered, washed with water, ether, and dried under vacuum. The crudeproduct was added to a silica gel column and eluted with heptane/EtOAc(0-100%) to provide4-(3-acrylamido-2-methylphenyl)-2-(4,4-difluorocyclohex-1-en-1-yl)-1H-indole-7-carboxamide(0.16 g, 74%): LC/MS (Table 1, Method g) R_(t)=3.02 min; MS m/z: 436(M+H)⁺. (BTK IC₅₀=A)

TABLE E.1 Examples prepared from acryloyl chloride using GeneralProcedure E R_(t) min (Table 1, m/z ESI+ Amine Product Example # Method)(M + H)⁺ Btk IC₅₀ 4-(2- (aminomethyl)phenyl)-2- (1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin- 4-yl)-1H-indole-7- carboxamide hydrochloride(prepared using A from Preparation #18 and tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)benzylcarbamate [JW] and G withHCl

E.1.1 1.47 (f) 479 A 4-(2-aminophenyl)-1H- indole-7-carboxamide (Example#A.5.1)

E.1.2 1.32 (f) 306 C 4-(2-aminopyridin-4-yl)- 1H-indole-7-carboxamide(Example #A.5.3)

E.1.3 0.96 (f) 307 A 4-(5-aminopyridin-3-yl)- 1H-indole-7-carboxamide(Example #A.5.4)

E.1.4 0.90 (f) 307 A 4-(3- (methylamino)phenyl)-1H- indole-7-carboxamide(prepared using A from Preparation #P.1 and 3-bromo-N-methylaniline)

E.1.5 1.41 (f) 320 A 4-(2-methyl-3- (methylamino)phenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and3-bromo-N,2- dimethylaniline [Beta Pharm])

E.1.6 1.45 (f) 334 B 4-(2-methyl-3-(thiazol-2- ylmethylamino)phenyl)-2-(1-(methylsulfonyl)- 1,2,3,6-tetrahydropyridin- 4-yl)-1H-indole-7-carboxamide (Example #H.2.1)

E.1.7 1.75 (g) 576 A 4-(3-amino-4- methoxyphenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 5-bromo-2-methoxyaniline)

E.1.8 0.63 (ae) 336 B 4-(3-amino-2- methylphenyl)-1H-pyrrolo[3,2-c]pyridine-7- carboxamide (prepared using A from Preparation#9 and 2-methyl-3-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)aniline[CombiBlocks])

E.1.9 1.94 (d) 321 A 4-(3-amino-2- methylphenyl)-1H-pyrrolo[3,2-c]pyridine-7- carboxamide (prepared using A from Preparation#9 and 3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)aniline)

E.1.10 2.04 (d) 307 A (R)-4-(3-aminopiperidin-1-yl)-2-(1-(methylsulfonyl)- 1,2,3,6-tetrahydropyridin- 4-yl)-1H-indole-7-carboxamide (prepared using B from Preparation #27 and (R)-tert-butylpiperidin- 3-ylcarbamate, N with Cs₂CO₃, G with HCl, and O)

E.1.11* 1.27 (F) 472 A 4-(3-amino-4- (benzyloxy)phenyl)-1H-indole-7-carboxamide (prepared using A Preparation #2 and Preparation#34)

E.1.12 3.18 (d) 412 C 4-(3-amino-4-(thiazol-2- ylmethoxy)phenyl)-1H-indole-7-carboxamide (prepared using R from Preparation #Q.1, A fromPreparation #P.1)

E.1.13 2.79 (D) 419 B 4-(3-amino-5-(thiazol-2- ylmethoxy)phenyl)-1H-indole-7-carboxamide (prepared using A Preparation #2 and Preparation#35)

E.1.14 2.80 (o) 412 C 4-(3-amino-5-(thiazol-2- ylmethoxy)phenyl)-1H-indole-7-carboxamide (prepared using S from 1-bromo-3-methoxy-5-nitrobenzene with BBr₃, Q from thiazol-2-ylmethanol, R with Fe, P with4,4,4′,4′,5,5,5′,5′- octamethyl-2,2′-bi(1,3,2- dioxaborolane), and Afrom Preparation #2

E.1.14 2.77 (d) 419 B 4-(2-amino-4-(thiazol-2- ylmethoxy)phenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 andPreparation #R.1)

E.1.16 2.77 (d) 419 C 4-(2-amino-4- (benzyloxy)phenyl)-1H-indole-7-carboxamide (prepared using R from Preparation #36 with Fe, andA from Preparation #P.1)

E.1.17 3.29 (d) 412 C 4-(3-aminophenyl)-2- ethyl-1H-indole-7-carboxamide (Example #20, Step C)

E.1.18 2.93 (d) 332 A 4-(3-amino-4- chlorophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 5-bromo-2-chloroaniline)

E.1.19 0.67 (ae) 340 A 4-(3-amino-2,6- difluorophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 3-bromo-2,4-difluoroaniline)

E.1.20 0.62 (ae) 342 A 4-(5-amino-2,3- difluorophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 3-bromo-4,5-difluoroaniline)

E.1.21 0.66 (ae) 342 A 4-(5-amino-2,4- difluorophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 5-bromo-2,4-difluoroaniline)

E.1.22 0.62 (ae) 342 A 4-(3-amino-4- fluorophenyyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 5-bromo-2-fluoroaniline)

E.1.23 0.62 (ae) 324 A 4-(5-amino-2- chlorophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and3-bromo-4-chloroaniline)

E.1.24 0.65 (ae) 340 A 4-(3-amino-4- methylphenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 5-bromo-2-methylaniline)

E.1.25 0.63 (ae) 320 A 4-(3-amino-5- cyanophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 3-bromo-3-cyanoaniline)

E.1.26 0.63 (ae) 331 B 4-(3-amino-2-cyano- phenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 3-bromo-2cyanoaniline)

E.1.27 0.58 (ae) 331 B 4-(3-amino-5- methoxyphenyl)-1H- indole-7-carboxamide (prepared using A from Preparation #P.1 and 3-bromo-5-methoxyaniline)

E.1.28 0.63 (ae) 336 B 4-(3-amino-5- methylphenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 3-bromo-5-methylaniline)

E.1.29 0.65 (ae) 320 B 4-(3-amino-2- methoxyphenyl)-1H-indole-7-carboxamide 2- (prepared using A from Preparation #P. 1 and 3-bromo-2-methoxyaniline)

E.1.30 0.63 (ae) 336 B 4-(3-amino-4- cyanophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 2-amino-4-bromobenzonitrile)

E.1.31 0.59 (ae) 331 A 4-(5-amino-2- fluorophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 3-bromo-4-fluoroaniline)

E.1.32 0.63 (ae) 324 B 4-(3-amino-2- fluorophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 3-bromo-2-fluoroaniline)

E.1.33 0.62 (ae) 324 A 4-(3-amino-2- fluorophenyl)-1H-indole-7-carboxamide (prepared using A from Preparation #P.1 and 3-bromo-2-fluoroaniline)

E.1.33 0.62 (ae) 324 A 4-(3-(N- (cyclopentylmethyl)acryla-mido)phenyl)-1H-indole-7- carboxamide (prepared using H from Preparation#A.1 and cyclopentanecarbaldehyde)

E.1.34 0.79 (ae) 388 C 4-(3-(N-iso- butylacrylamido)phenyl)-1H-indole-7- carboxamide (prepared using H from Preparation #A.1 andisobutyraldehyde)

E.1.35 0.75 (ae) 362 B

TABLE E.2 Examples prepared from4-(3-aminophenyl)-1H-indole-7-carboxamide (Preparation #A.1) usingGeneral Procedure E Exam- R_(t) min m/z ple (Table 1, ESI+ Btk AcidChloride Product # Method) (M + H)⁺ IC₅₀ 5-methylisoxazole-4- carbonylchloride

E.2.1 2.61 (c) 361 C 1-methyl-1,2,5,6- tetrahydropyridine-3- carbonylchloride hydrochloride [J. Med. Chem., 1980, 23 (8) 865]

E.2.2 1.36 (f) 375 C

TABLE E.3 Examples prepared from4-(2-aminophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide (Example #A.4.2) usingGeneral Procedure E Exam- R_(t) min m/z Acid ple (Table 1, ESI+ BtkChloride Product # Method) (M + H)⁺ IC₅₀ acetyl chloride

E.3.1 1.41 (f) 453 B

TABLE E.4 Examples prepared fromN-(3-(2-(2-(aminomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide (Example #1) using GeneralProcedure E Acid Chloride Exam- R_(t) min m/z or ple (Table 1, ESI+ BtkAnhydride Product # Method) (M + H)⁺ IC₅₀ 2-chloroacetyl chloride

E.4.1 3.17 (d) 558 B propionyl chloride

E.4.2 3.10 (d) 538 C acetic anhydride

E.4.3 3.01 (d) 524 B

TABLE E.5 Examples prepared fromN-(3-(3-amino-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide (Preparation #7) using GeneralProcedure E Acid Exam- R_(t) min m/z Chloride or ple (Table 1, ESI+ BtkAnhydride Product # Method) (M + H)⁺ IC₅₀ 2-chloro- acetyl chloride

E.5.1 2.79 (d) 468 C

TABLE E.6 Examples prepared from ethyl carbono-chloridate using GeneralProcedure E Exam- R_(t) min m/z ple (Table 1, ESI+ Btk Amine Product #Method) (M + H)⁺ IC₅₀ 2-(2,5- dihydro- 1H- pyrrol- 3-yl)-4- (2-methyl-3-(4-oxo- quinazolin- 3(4H)- yl)phenyl)- 1H-indole- 7-carbox- amide(Example #G.1)

E.6.1 2.74 (o) 534 A 4-(2- methyl-3- (4-oxo- quinazo- lin-3(4H)-yl)phenyl)- 2-(1,2,3,6- tetrahydro- pyridin-4- yl)-1H- indole-7- carbox-amide (Example #G.1.1)

E.6.2 2.82 (o) 548 A

TABLE E.7 Examples prepared from 2-oxopropanoyl chloride (prepared frompyruvic aicd and 1,1-dichlorodimethyl ether [Synthesis, 1975, 3163-164]) using General Procedure E Exam- R_(t) min m/z ple (Table 1,ESI+ Btk Amine Product # Method) (M + H)⁺ IC₅₀ 4-(3-aminophenyl)-1H-indole-7-carboxamide (Preparation #A.1)

E.7.1 1.47 (g) 322 B 4-(3- (aminomethyl)phenyl)- 1H-indole-7-carboxamide(prepared using A from (3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride with 4- bromo-1H-indole-7-carboxamide [Preparation #2])

E.7.2 1.41 (g) 336 B

TABLE E.8 Examples prepared from acetyl chloride using General ProcedureE Exam- R_(t) min m/z ple (Table 1, ESI+ Btk Acid Chloride Product #Method) (M + H)⁺ IC₅₀ 2-(2,5-dihydro-1H-pyrrol- 3-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)- yl)phenyl)-1H-indole-7- carboxamide (Example #G.1)

E.8.1 2.72 (d) 504 A 4-(2-methyl-3-(4- oxoquinazolin-3(4H)-yl)phenyl)-2-(1,2,3,6- tetrahydropyridin-4-yl)- 1H-indole-7-carboxamide(Example #G.1.1)

E.8.2 1.78 (a) 518 A

TABLE E.9 Examples prepared from acryloyl chloride with an amine usingGeneral Procedure E Exam- R_(t) min m/z ple (Table 1, ESI+ Btk AmineProduct # Method) (M + H)⁺ IC₅₀ 4-(2- (Aminomethyl)phenyl)-2-(1-(methylsulfonyl)- 1,2,3,6-tetrahydropyridin- 4-yl)-1H-indole-7-carboxamide hydrochloride (prepared using A from Preparation #18 withtert-butyl 2-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)benzylcarbamate [JW] and G with HCl)

E.9.1 1.47 (f) 479 A 4-(Azetidin-3- yl(methyl)amino)-2-cyclopropyl-1H-indole- 7-carboxamide (prepared using A from Preparation#40 with Cyclopropylboronic acid [SCRC] and G with HCl)

E.9.2 1.38 (aa) 339 A 4-(Azetidin-3- yl(methyl)amino)-2-(isochroman-7-yl)-1H- indole-7-carboxamide (prepared using A fromPreparation #40 with 2-(isochroman-7-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane [prepared using P and 7-bromoisochroman] and G with HCl)

E.9.3 1.44 (aa) 431 A 4-(Azetidin-3- yl(methyl)amino)-2-(6,7-dihydro-4H-pyrazolo[5,1- c][1,4]oxazin-2-yl)-1H- indole-7-carboxamide(Prepared using P from preparation #40, Step A with4,4,5,5-tetramethyl-1,3,2- dioxaborolane, A with Preparation #44, C withLiOH, D with NH₄Cl and G with HCl)

E.9.4 1.46 (a) 421 A 4-(Azetidin-3- yl(methyl)amino)-2-(4,4-difluorocyclohex-1-en-1- yl)-1H-indole-7- carboxamide (prepared using Afrom Preparation #40 with 2-(4,4-difluorocyclohex- 1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane [Syngene] and G with HCl)

E.9.5 1.53 (aa) 415 A 4-(Azetidin-3- yl(methyl)amino)-2-(4-(methylsulfonyl)cyclohex- 1-en-1-yl)-1H-indole-7- carboxamidehydrochloride (prepared using A from Preparation #40 with4,4,5,5-tetramethyl-2-(4- (methylsulfonyl)cyclohex- 1-en-1-yl)-1,3,2-dioxaborolane (WO2005/73206 A1) and G with HCl

E.9.6 1.44 (ab) 457 A (S)-2-Methyl-4-(piperidin- 3-yl)-1H-indole-7-carboxamide hydrochloride (prepared using X from Preparation #39 withLiOH, D with NH₄Cl, L with Pd/C, chiral separation (Table 2, Method 5)and G with HCl)

E.9.7 1.58 (a) 312 A (R)-2-Methyl-4-(piperidin- 3-yl)-1H-indole-7-carboxamide hydrochloride (prepared using X from Preparation #39 withLiOH, D with NH₄Cl, L with Pd/C, chiral separation (Table 2, Method 5)and G with HCl)

E.9.8 1.64 (a) 312 A 4-(Azetidin-3- yl)(methyl)amino)-2-(6-morpholinopyridin-3-yl)- 1H-indole-7-carboxamide (Prepared using A fromPreparation #40 with 4-(5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine and G with HCl)

E.9.10 1.22 (at) 461 A 4-(Azetidin-3- yl(methyl)amino)-2-(7,8-dihydro-5H-pyrano[4,3- b]pyridin-3-yl)-1H-indole- 7-carboxamidehydrochloride (Prepared using A from Preparation #40 with(7,8-dihydro-5H- pyrano[4,3-b]pyridin-3- yl)boronic acid [Anichem]) andG with HCl)

E.9.11 1.48 (au) 432 A 4-(Azetidin-3- yl(methyl)amino)-2-(chroman-7-yl)-1H- indole-7-carboxamide hydrochloride (Prepared using Pfrom 7-bromochroman [Arkpharm] with bis(pinacolato)diboron, A withPreparation #40 and G with HCl)

E.9.12 1.51 (av) 431 A 4-(Azetidin-3- yl)(methyl)amino)-2-(5-(morpholinomethyl) pyridin-2-yl)-1H-indole-7- carboxamide (Preparedusing G from Preparation #48 with HCl)

E.9.13 1.60 (aw) 475 A 4-(Azetidin-3- yl(methyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)- 1H-indole-7-carboxamide hydrochloride (Preparedusing A from Preparation #40 with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H- pyrazole and G withHCl)

E.9.14 1.51 (aw) 379 A 4-(Azetidin-3- yl(methyl)amino)-2-(3,4-dihydro-2H-benzo[b] [1,4]oxazin-6-yl)- 1H-indole-7-carboxamidedihydrochloride (Prepared using A from Preparation #40 with tert- butyl3-((7-carbamoyl-2- iodo-1H-indol-4-yl) (methyl)amino)azetidine-1-carboxylate [Arkpharminc] and G with HCl)

E.9.15 1.37 (av) 432 A 4-(Azetidin-3- yl(methyl)amino)-2-(1-methyl-1H-pyrazol-5-yl)- 1H-indole-7-carboxamide hydrochloride (Preparedusing A from Preparation #40 with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H- pyrazole and G withHCl)

E.9.16 1.28 (be) 379 A 4-(Azetidin-3- yl(methyl)amino)-2-(2-ethyl-1,2,3,4- tetrahydroisoquinolin-6- yl)-1H-indole-7- carboxamidehydrochloride (Prepared using A from Preparation #40 with 1-methyl-5-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-1H- pyrazoleand G with HCl)

E.9.17 1.12 (av) 458 A 4-(Azetidin-3- yl(methyl)amino)-2-(1,3-dimethyl-1H-pyrazol-4- yl)-1H-indole-7- carboxamide hydrochloride(Prepared using A from Preparation #40 with 1,3- dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H- pyrazole and G with HCl)

E.9.18 1.29 (av) 393 A 4-(Azetidin-3- yl(methyl)amino)-2-(1,1-dioxidotetrahydro-2H- thiopyran-4-yl)-1H-indole- 7-carboxamidehydrochloride (Prepared using A from Preparation #40 with 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6- dihydro-2H-thiopyran1,1-dioxide [JWpharmlab], L with Pd/C and G with HCl)

E.9.19 1.41 (aw) 431 A 4-(Azetidin-3- yl)(methyl)amino)-2-(1-propylpiperidin-4-yl)-1H- indole-7-carboxamide (Prepared using J from 1-iodopropane with 4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine [Arkpharminc], A with Preparation #40, L withPd/C and G with HCl)

E.9.20 1.10 (av) 424 A 4-(Azetidin-3- yl)(methyl)amino)-2-(tetrahydrofuran-3-yl)-1H- indole-7-carboxamide (Preparation #41)

E.9.21 1.28 (av) 369 A 4-(Azetidin-3- yl(methyl)amino)-2-(3-hydroxyoxetan-3-yl)-1H- indole-7-carboxamide 2,2,2-trifluoroacetate(Prepared using X from Preparation # 42 with KOH, D with NH₄Cl and Gwith TFA)

E.9.22 1.18 (ay) 372 B (R)-2-(1-Methyl-1H- pyrazol-4-yl)-4-(morpholin-2-yl)-1H- indole-7-carboxamide hydrochloride (Prepared usingY from Preparation #43, A with 1- methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole [Arkpharm], O, chiral separation (Table2, Method 4) and G with HCl)

E.9.23 1.40 (a) 380 A (S)-2-(1-Methyl-1H- pyrazol-4-yl)-4-(morpholin-2-yl)-1H- indole-7-carboxamide hydrochloride (Prepared usingY from Preparation #43, A with 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole [Arkpharm], O, chiral separation (Table2, Method 4) and G with HCl))

E.9.24 1.36 (a) 380 A 4-(Azetidin-3- yl(methyl)amino)-2-methyl-1H-indole-7- carboxamide hydrochloride (Prepared using A fromPreparation #40 with methylboronic acid and G with HCl)

E.9.25 1.30 (az) 313 A (R)-2-(6,7-Dihydro-4H- pyrazolo[5,1-c][1,4]oxazin-2-yl)-4- (pyrrolidin-3-yl)-1H- indole-7-carboxamide(Prepared using P from Preparation #Y.1 with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, A with Preparation #44, chiral separation (Table 2,Method 6), C with LiOH, D with NH₃ and G with HCl)

E.9.26 1.58 (ba) 406 A (S)-2-(6,7-Dihydro-4H- pyrazolo[5,1-c][1,4]oxazin-2-yl)-4- (pyrrolidin-3-yl)-1H- indole-7-carboxamide(Prepared using P from Preparation #Y.1 with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, A with Preparation #44, chiral separation (Table 2,Method 6), C with LiOH, D with NH₃ and G with HCl)

E.9.27 1.58 (ba) 406 A (R)-4-(1-(Azetidin-3- yl)ethyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide (prepared using AA from tert-butyl 3-acetylazetidine-1- carboxylate [JWpharm] with N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N- ((trifluoromethyl)sulfonyl) methane sulfonamide, Wwith 4,4,4′,4′,5,5,5′,5′- octamethyl-2,2′-bi(1,3,2- dioxaborolane)], Awith Preparation #37, L with Pd/C, C with LiOH, D

E.9.28 1.03 (a) 299 A with NH₄Cl, chiral separation (Table 2, Method 7)and G with HCl) (S)-4-(1-(Azetidin-3- yl)ethyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide (prepared using AA from tert-butyl 3-acetylazetidine-1- carboxylate [JWpharm] with N-(5- chloropyridin-2-yl)-1,1,1-trifluoro-N- ((trifluoromethyl)sulfonyl) methane sulfonamide, Wwith 4,4,4′,4′,5,5,5′,5′- octamethyl-2,2′-bi(1,3,2- dioxaborolane)], Awith Preparation #37, L with Pd/C, C with LiOH, D

E.9.29 0.99 (a) 299 B with NH₄Cl, chiral separation (Table 2, Method 7)and G with HCl) 4-((R)-1,4-Oxazepan-6- yl)-7,7a-dihydro-1H-pyrrolo[3,2-c]pyridine-7- carboxamide (prepared using C from Preparation#AH.1 with LiOH, D with NH₄Cl, L with Pd(OH)₂, chiral separation (Table2, Method 8) and G with HCl)

E.9.30 0.97 315 (a) A 4-((S)-1,4-Oxazepan-6- yl)-7,7a-dihydro-1H-pyrrolo[3,2-c]pyridine-7- carboxamide (prepared using C from Preparation#AH.1 with LiOH, D with NH₄Cl, L with Pd(OH)₂, chiral separation (Table2, Method 8) and G with HCl)

E.9.31 0.97 (as) 315 C (R)-4-(Piperidin-3-yl)-1H-pyrrolo[3,2-c]pyridine-7- carboxamide hydrochloride (prepared using Zfrom Preparation #AB.1, chiral separation (Table 2, Method 9) and G withHCl)

E.9.32 1.04 (as) 299 A (S)-4-(Piperidin-3-yl)-1H-pyrrolo[3,2-c]pyridine-7- carboxamide hydrochloride (prepared using Zfrom Preparation #AB.1, chiral separation (Table 2, Method 9) and G withHCl)

E.9.33 1.04 (a) 299 B 4-(Azetidin-3-ylamino)- 1H-pyrrolo[2,3-c]pyridine-7-carboxamide (prepared using O from Preparation #AD.1, T withtert-butyl 3- aminoazetidine-1- carboxylate[arkpharm] and G with HCl)

E.9.34 1.10 (ba) 286 A tert-Butyl 3-((7- carbamoyl-1H-indol-4-yl)(methyl)amino)-3- methylazetidine-1- carboxylate (Prepared using Tfrom Preparation #1, Step C and tert-butyl 3-amino-3- methylazetidine-1-carboxylate [AKSCI], J withCH₃I, X with LiOH, D with NH₄Cl and G withHCl)

E.9.35 1.47 (a) 313 A (R)-2-(1-Methyl-1H- pyrazol-4-yl)-7-(piperidin-3-yl)thiazolo[5,4- c]pyridine-4-carboxamide (Prepared using A fromPreparation #46 with tert-butyl 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-1(2H)- carboxylate, L with Pd/C,chiral separation (Table 2, Method 10) and G with HCl)

E.9.36 1.62 (as) 397 A (S)-2-(1-Methyl-1H- pyrazol-4-yl)-7-(piperidin-3-yl)thiazolo[5,4- c]pyridine-4-carboxamide (Prepared using A fromPreparation #46 with tert-butyl 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-1(2H)- carboxylate, L with Pd/C,chiral separation (Table 2, Method 10) and G with HCl)

E.9.37 1.60 (as) 397 A (S)-4-(1,4-Oxazepan-6-yl)-1H-indole-7-carboxamide (prepared using AA with tert-butyl 6-oxo-1,4-oxazepane-4- carboxylate[Arkpharm] and 1,1,1-trifluoro-N- phenyl-N-((trifluoromethyl)sulfonyl) methane sulfonamide, A with Preparation#P.1, L with Pd/C, chiral separation (Table 2, Method 11) and G withHCl)

E.9.38 1.34 (a) 314 A (R)-4-(1,4-Oxazepan-6-yl)- 1H-indole-7-carboxamide(prepared using AA with tert-butyl 6-oxo-1,4- oxazepane-4-carboxylate[Arkpharm] and 1,1,1-trifluoro-N- phenyl-N-((trifluoromethyl)sulfonyl) methane sulfonamide, A with Preparation#P.1, L with Pd/C, chiral separation (Table 2, Method 11) and G withHCl)

E.9.39 1.33 (a) 314 C (S)-2-Methyl-4- (pyrrolidin-3-yl)-1H-indole-7-carboxamide (Prepared using chiral separation (Table 2, Method3) from Preparation #38, C with LiOH, D with NH₃ and G with HCl)

E.9.40* 1.52 (ba) 298 B (R)-2-Methyl-4- (pyrrolidin-3-yl)-1H-indole-7-carboxamide (Prepared using chiral separation (Table 2, Method3) from Preparation #38, C with LiOH, D with NH₃ and G with HCl)

E.9.41* 1.60 (ba) 298 B 4-((1S,5S)-3,6- Diazabicyclo[3.2.0]heptan-3-yl)-1H-indole- 7-carboxamide (Prepared using A from 4-bromo-1H-indole-7- carboxamide[Anthem] with tert-butyl 3,6-diazabicyclo[3.2.0] heptane-6-carboxylate [Arkpharm], chiral separation(Table 2, Method 13) and G with HCl)

E.9.42 1.39 (ba) 311 B 4-((1R,5R)-3,6- Diazabicyclo[3.2.0]heptan-3-yl)-1H-indole- 7-carboxamide (Prepared using A from 4-bromo-1H-indole-7- carboxamide[Anthem] with tert-butyl 3,6-diazabicyclo[3.2.0] heptane-6-carboxylate [Arkpharm], chiral separation(Table 2, Method 13) and G with HCl)

E.9.43 1.40 (ba) 311 B 4-((3S,5R)-5- (Hydroxymethyl) piperidin-3-yl)-1H-indole-7-carboxamide (Prepared using chiral separation (Table 2, Method14) from Preparation #AE.1 and G with HCl)

E.9.44 1.31 (ba) 328 B 4-((3S,5S)-5- (Hydroxymethyl) piperidin-3-yl)-1H-indole-7-carboxamide (Prepared using chiral separation (Table 2, Method14) from Preparation #AE.1 and G with HCl)

E.9.45 1.29 (ba) 328 C 4-(5- (Hydroxymethyl) piperidin-3-yl)-1H-indole-7-carboxamide (Prepared using chiral separation (Table 2, Method14) from Preparation #AE.1 and G with HCl)

E.9.46 1.34 (ba) 328 C 4-(5- (Hydroxymethyl) piperidin-3-yl)-1H-indole-7-carboxamide (Prepared using chiral separation (Table 2, Method14) from Preparation #AE.1 and G with HCl)

E.9.47 1.30 (ba) 328 B (R)-2-(1-Methyl-1H- pyrazol-4-yl)-4-(pyrrolidin-3-yl)-1H- indole-7-carboxamide hydrochloride (Prepared usingA from Preparation #Y.1 with 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole[arkpharm], chiral separation (Table 2,Method 17), C with LiOH, D with NH₃ and G with HCl)

E.9.48 1.39 (a) 364 A (S)-2-(1-Methyl-1H- pyrazol-4-yl)-4-(pyrrolidin-3-yl)-1H- indole-7-carboxamide (Prepared using A fromPreparation #Y.1 with 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole[arkpharm], chiral separation (Table 2,Method 17), C with LiOH, D with NH₃ and G with HCl)

E.9.49 1.50 (ba) 364 B 4-((1R,3R)-3- Aminocyclopentyl)-1H-indole-7-carboxamide hydrochloride (Prepared using C from Preparation#47 with LiOH, D with NH₄Cl and G with HCl)

E.9.50 1.43 (a) 298 A (S)-4-(Piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridine-7- carboxamide (Prepared using A from Example#29, Step A with tert-butyl 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-1(2H)- carboxylate, O, L withPd/C, chiral separation (Table 2, Method 18) and G with acetyl chloride)

E.9.51 1.42 (ba) 299 B (R)-4-(Piperidin-3-yl)-1H-pyrrolo[2,3-c]pyridine-7- carboxamide (Prepared using A from Example#29, Step A with tert-butyl 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-1(2H)- carboxylate, O, L withPd/C, chiral separation (Table 2, Method 18) and G with acetyl chloride)

E.9.52 1.43 (ba) 299 B

TABLE E.9.1 Examples prepared from acryloyl chloride with an amine usingGeneral Procedure E Exam- R_(t) min m/z ple (Table 1, (M + H₂O + BtkAmine Product # Method) H)⁺ IC₅₀ 4-(Azetidin-3- yl(methyl)amino)-2-(3-hydroxyoxetan-3-yl)-1H- indole-7-carboxamide 2,2,2-trifluoroacetate(Prepared using X from Preparation # 42 with KOH, D with NH₄Cl and Gwith TFA)

E.9.1.1 1.18 (ay) 353 B

TABLE E.10 Examples prepared from propionyl chloride with an amine usingGeneral Procedure E R_(t) min (Table 1, m/z ESI+ Btk Amine ProductExample # Method) (M + H)⁺ IC₅₀ (R)-2-Methyl-4- (pyrrolidin-3-yl)-1H-indole-7-carboxamide (Prepared using chiral separation (Table 2, Method12) from Preparation #38, C with LiOH, D with NH₃ and G with HCl)

E.10.1 1.64 (ba) 300 B (S)-2-Methyl-4- (pyrrolidin-3-yl)-1H-indole-7-carboxamide (Prepared using chiral separation (Table 2, Method12) from Preparation #38, C with LiOH, D with NH₃ and G with HCl)

E.10.2 1.63 (ba) 300 B

General Procedure F: Formation of a4-iodoindole-7-carboxamide

To a solution of 2-amino-4-nitrobenzoic acid (preferably 1equiv) in MeOHis added slowly concentrated sulfuric acid (preferably 1equiv). Theresulting solution is heated at about 75° C. for about 3 days. Aftercooling, the reaction is neutralized by addition of aqueous NaOHsolution until pH-10. The reaction is extracted with EtOAc, dried overanhydrous sodium sulfate, filtered and concentrated. To thisintermediate (preferably 1equiv) is added a methyl ketone (1-2 equiv,preferably 2 equiv) and an organic solvent (preferably dimethylsulfoxide). The reaction is cooled to about −15° C. A base (preferablypotassium tert-butoxide 2 equiv) is added. After stirring for about 2.5h at rt, the reaction is quenched with saturated aqueous ammoniumchloride solution and then stirred for about 1 h at rt. The resultingsuspension was filtered, washed with water and the solid is dried underhigh vacuum. To this intermediate (preferably 1 equiv) is added((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphoniumhexafluorophosphate(V) (preferably 2 equiv), hydroxybenzotriazolehydrate (preferably 2 equiv) and ammonium chloride (preferably 1.5equiv) and an organic solvent (preferably DMF). An organic base(preferably diisopropylethylamine, 4 equiv) is added. The reactionmixture is stirred at rt overnight. The mixture is poured into water andthe resulting precipitate is filtered, washed with water and EtOAc, andcollected. To this intermediate (preferably 1 equiv) is added an organicsolvent (preferably MeOH), and the solution is purged with nitrogen. Tothis solution is added 10% palladium on carbon (preferably 0.1 equiv).The resulting suspension is treated with hydrogen (30 psi). Afterstirring overnight at rt, the reaction is filtered, and the solids arerinsed with MeOH. The filtrate is concentrated. A solution of sodiumnitrite (preferably 2.2 equiv) in water is added to an ice coldsuspension of this intermediate (preferably 1 equiv) in an organicsolvent (preferably MeCN) and 2N HCl (preferably 5.4 equiv) withstirring, maintaining the temperature below about −5° C. After stirringfor about 30 min, a cold solution of aqueous potassium iodide(preferably 2.5 equiv) is added to the reaction and the resultingmixture was stirred at rt for about 30 min. The reaction is heated toabout 85° C. for about 5 min. The reaction is cooled to rt andneutralized with saturated aqueous sodium bicarbonate to pH 8. Themixture is extracted with DCM. The organic layer is washed with brine,dried over sodium sulfate, filtered and concentrated. The residue ispurified by flash chromatography (preferably silica gel, petroleumether) to give the target compound.

Illustration of General Procedure F Example #F.1:4-Iodo-2-(pyridin-3-yl)-1H-indole-7-carboxamide

To a solution of 2-amino-4-nitrobenzoic acid (102 g, 560 mmol) in MeOH(1.5 L) was added slowly concentrated sulfuric acid (0.030 L, 560 mmol).The resulting solution was heated at about 75° C. for about 3 days.After cooling, the product was neutralized by addition of aqueous NaOHsolution until pH˜10. The crude product was extracted with EtOAc, driedover anhydrous sodium sulfate, filtered and concentrated to providemethyl 2-amino-4-nitrobenzoate (100 g, 91%). LC/MS (Table 1, Method ar)R_(t)=1.85 min; MS m/z 197.1 (M+H)⁺. To a portion of this material (25g, 127 mmol) and 1-(pyridin-3-yl)ethanone (30.9 g, 255 mmol) in dimethylsulfoxide (150 mL) at about −15° C. was added potassium tert-butoxide(28.6 g, 255 mmol). After stirring for about 2.5 h at rt, the reactionwas quenched with saturated aqueous ammonium chloride solution (100 mL)and then stirred for about 1 hr at rt. The resulting suspension wasfiltered, washed with water and dried under high vacuum to provide4-nitro-2-(pyridin-3-yl)-1H-indole-7-carboxylic acid (22.4 g, 34%).LC/MS (Table 1, Method ab) R_(t)=1.50 min; MS m/z 284.1 (M+H)⁺. To amixture of this material (26.9 g, 95 mmol),((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphoniumhexafluorophosphate(V) (99 g, 190 mmol), hydroxybenzotriazole hydrate(29.1 g, 190 mmol) and ammonium chloride (7.62 g, 142 mmol) in DMF (150mL) was added diisopropylethylamine (66.3 mL, 380 mmol). The reactionmixture was stirred at rt overnight. The mixture was poured into 1000 mLwater and the precipitate was filtered, washed with water and EtOAc, andcollected to provide 4-nitro-2-(pyridin-3-yl)-1H-indole-7-carboxamide(17.48 g, 56%). LC/MS (Table 1, Method ar) R_(t)=1.44 min; MS m/z 283.1(M+H)⁺. To a nitrogen-purged stirred solution of this material (17.5 g,52.6 mmol) in MeOH (1.5 L) was added 10% palladium on carbon (5.60 g,5.26 mmol). The resulting suspension was treated with hydrogen (30 psi).After stirring overnight at rt, the reaction was filtered, and thesolids were rinsed with MeOH. The filtrate was concentrated to provide4-amino-2-(pyridin-3-yl)-1H-indole-7-carboxamide (10 g, 75%). LC/MS(Table 1, Method ar) R_(t)=1.10 min; MS m/z 253.1 (M+H)⁺. A solution ofsodium nitrite (7.82 g, 113 mmol) in water (20 mL) was added to an icecold suspension of this material (13 g, 51.5 mmol) in MeCN (150 mL) and2N hydrogen chloride (188 mL, 376 mmol) with stirring, maintaining thetemperature below about −5° C. After stirring for about 30 min, a coldsolution of aqueous potassium iodide (21.4 g, 129 mmol) was added to thereaction and the resulting mixture was stirred at rt for about 30 min.The reaction was heated on a water bath (85° C.) for 5 min. The reactionwas cooled to rt and neutralized with saturated aqueous sodiumbicarbonate to pH 8. The mixture was extracted with DCM. The organiclayer was washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue was purified by flash chromatography (silicagel, petroleum ether) to provide4-iodo-2-(pyridin-3-yl)-1H-indole-7-carboxamide (2.0 g, 9%). LC/MS(Table 1, Method ab) R_(t)=1.88 min; MS m/z 364.0 (M+H)⁺. (Btk IC₅₀=B)

General Procedure G: Acidic Cleavage of a Boc-Protected Amine

To a solution of an N-Boc amine (1 equiv) in an organic solvent (such asDCM, DCE, 1,4-dioxane, EtOAc, or MeOH, preferably DCM, EtOAc, or1,4-dioxane) is added an acid (such as TFA or HCl, preferably TFA; 2 to35 equiv, preferably 15 to 25 equiv). The mixture is stirred at about 0to 100° C. (preferably about 20 to 60° C.) for about 1 to 24 h(preferably about 1 to 6 h). Optionally, additional acid (2 to 35 equiv,preferably 20 to 25 equiv) may be added and the mixture stirred at about0 to 100° C. (preferably about 15 to 60° C.) for about 1 to 24 h(preferably about 1 to 6 h). If a solid is present in the mixture, themixture may be optionally filtered and the solid washed with an organicsolvent such as 1,4-dioxane or Et₂O. The resulting solid is thenoptionally dried under reduced pressure to give the targeted compound.Alternatively, the mixture may be optionally concentrated in vacuo togive final compound. Alternatively, the mixture is optionally filteredthrough a media (such as silica gel or Celite®) which is rinsed with anappropriate solvent (such as EtOAc, 1,4-dioxane, THF, MeCN, DCM, Et₂O,MeOH, EtOH) and then optionally concentrated in vacuo to give a residue.Either the residue or the solution may be optionally partitioned betweenwater and an organic solvent (such as EtOAc, Et₂O or DCM). The organiclayer is isolated and may be optionally washed in no particular orderwith water and/or aqueous solutions containing an acid (such as HCl,AcOH or NH₄Cl) and/or aqueous solutions containing a base (such asNaHCO₃, Na₂CO₃, NaOH, KOH or NH₄OH) and/or aqueous solutions containingan inorganic salt (such as NaCl Na₂SO₃ or Na₂S₂O₃). The organic solutionmay then be optionally dried with a drying agent (such as anhydrousMgSO₄ or Na₂SO₄), filtered and concentrated in vacuo to give thetargeted compound.

Illustration of General Procedure G Example #G.1.2-(2,5-Dihydro-1H-pyrrol-3-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide

To a solution of tert-butyl3-(7-carbamoyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(0.6 g, 1 mmol, Preparation #15) in EtOAc (20 mL) was added HC/EtOAc atrt. The reaction mixture was stirred at rt for 1 h. The solid wascollected as a salt via filtration and dried to give2-(2,5-dihydro-1H-pyrrol-3-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamidehydrochloride (0.5 g, 94%): LC/MS (Table 1, Method d) R_(t)=2.39 min; MSm/z: 462 (M+H)⁺ (Btk IC₅₀=A).

TABLE G.1 Examples prepared using General Procedure G R_(t) min (Table1, m/z ESI+ Btk N-Boc Amine Product Example # Method) (M + H)⁺ IC₅₀tert-butyl 4-(7-carbamoyl- 4-(2-methyl-3-(4- oxoquinazolin-3(4H)-yl)phenyl)-1H-indol-2-yl)- 5,6-dihydropyridine- 1(2H)-carboxylate(Preparation #2)

G.1.1 2.13 (o) 476 A di-tert-butyl (2-((3-(7- carbamoyl-1H-indol-4-yl)phenyl)carbamoyl)allyl) carbamate (prepared using J from 2-(bromomethyl)acrylic acid and di-tert-butyl iminodicarboxylate, D fromPreparation #A.1)

G.1.2 2.17 (d) 335 A tert-butyl (2-((3-(7- carbamoyl-1H-indol-4-yl)phenyl)carbamoyl)allyl)- (methyl)carbamate (prepared using J from 2-(bromomethyl)acrylic acid and tert-butyl methylcarbamate, D fromPreparation #A.1)

G.1.3 2.20 (d) 349 A

General Procedure H: Reductive Amination of an Aldehyde or Ketone with aPrimary or Secondary Amine

An aldehyde or ketone (preferably 1.0 equiv to 1.3 equiv) and an amineor amine salt (preferably 1.0 to 2.2 equiv) are added in an organicsolvent or mixture of organic solvents (such as DCM, DCE or MeOH, or amixture of DCE and MeOH, preferably DCE, MeOH, or 1:1MeOH/DCM) at aboutrt to about 80° C. (preferably about rt). If an amine salt is used, thenan amine base (such as TEA or DIEA, 1.0 to 2.2 equiv) is optionallyadded. AcOH (0.1 equiv to 5.0 equiv) is optionally added. The mixture isstirred at rt for about 1 to 90 min (preferably 5 to 30 min). A reducingagent (such as NaBH(OAc)₃, Na(CN)BH₃, NaBH₄, MP-Cyanoborohydride fromBiotage™, 0.5 to 5.0 equiv, preferably 2.5-3.0 equiv of NaBH(OAc)₃), isadded as a solid or as a solution in an organic solvent (as DCM, DCE orMeOH, or a mixture of DCE and MOH). The mixture is stirred at rt forabout 30 min to 72 h (preferably 1 to 24 h). The crude mixture may beconcentrated under reduced pressure or optionally partitioned betweenwater and an organic solvent (such as EtOAc, Et₂O or DCM). The organiclayer is isolated and may be optionally washed with water and/or aqueoussolutions containing an acid (such as HCl, AcOH or NH₄Cl) and/or aqueoussolutions containing a base (such as NaHCO₃, Na₂CO₃, NaOH, KOH or NH₄OH)and/or aqueous solutions containing an inorganic salt (such as NaCl orNa₂SO₃). The organic solution may then be optionally dried with a dryingagent (such as MgSO₄ or Na₂SO₄), filtered and concentrated in vacuo togive the target compound.

Illustration of General Procedure H Example #H.1.2-(1-Methyl-2,5-dihydro-1H-pyrrol-3-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide

To a solution of2-(2,5-dihydro-1H-pyrrol-3-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(50 mg, 0.1 mmol, Example #G.1) in MeOH (1 mL) was added (CH₂O) (1.6 mg,0.054 mmol) at rt. After stirring at rt for 1 h under N₂ atmosphere,NaBH(OAc)₃ (60 mg, 0.27 mmol) was added. The resulting mixture wasstirred at rt for 2 h. The solvent was removed under reduced pressure togive a residue, which was purified by prep-HPLC to give2-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(15 mg, 32%): LC/MS (Table 1, Method o) R_(t)=2.05 min; MS m/z: 476(M+H)⁺ (Btk IC₅₀ A).

TABLE H.1 Examples prepared from4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide (Example #G.1.1) usingGeneral Procedure H R_(t) min (Table 1, m/z ESI+ Btk Aldehyde ProductExample # Method) (M + H)⁺ IC₅₀ paraformaldehyde

H.1.1 2.08 (o) 490 A

TABLE H.2 Examples prepared from4-(3-amino-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide (Example #A.4.5) usingGeneral Procedure H R_(t) min (Table 1, m/z ESI+ Btk Aldehyde ProductExample # Method) (M + H)⁺ IC₅₀ thiazole-2- carbaldehyde

H.2.1 1.74 (g) 522 A

General Procedure I: Formation of a Sulfonamide from an Amine and aSulfonyl Chloride

To a flask is added an amine (1.0 equiv), optionally as a hydrochloridesalt, a solvent or mixture of solvents (such as DCM, DCE, EtOAc, THF,1,4-dioxane, pyridine, DME, or pyridine/DCM, preferably THF, optionallywith a base (such as TEA, DIEA, preferably DIEA; 1 to 5 equiv,preferably 1-2 equiv) and a sulfonyl chloride (0.9 to 2.0 equiv,preferably 1.0 to 1.25 equiv). The mixture is stirred at about 0 to 80°C. (preferably about 0 to 35° C.) for about 1 h to 24 h (preferably 5 to16 h). The mixture may optionally be concentrated in vacuo to give aresidue as the target compound. Either the residue or the solution maybe optionally partitioned between water and an organic solvent (such asEtOAc, Et₂O or DCM). The organic layer is isolated and may optionally bewashed in no particular order with water and/or aqueous solutionscontaining an acid (such as HCl, AcOH or NH₄Cl) and/or aqueous solutionscontaining a base (such as NaHCO₃, Na₂CO₃, NaOH, KOH or NH₄OH) and/oraqueous solutions containing an inorganic salt (such as NaCl Na₂SO₃ orNa₂S₂O₃). The organic solution may then be optionally dried with adrying agent (such as anhydrous MgSO₄ or Na₂SO₄), filtered andconcentrated in vacuo to give the target compound.

Illustration of General Procedure I Example #I.1:4-(3-(Vinylsulfonamido)phenyl)-1H-indole-7-carboxamide

To a mixture of 4-(3-aminophenyl)-1H-indole-7-carboxamide (0.11 g, 0.438mmol, Preparation #A.1), THF (4 mL) and DIEA (0.152 mL, 0.876 mmol) atabout 0° C. (ice bath) was added ethenesulfonyl chloride (0.058 g, 0.460mmol, FCH Group). The ice bath was removed and mixture was stirred forabout 6 h at rt. The reaction mixture was concentrated under reducedpressure and the residue was dissolved in DCM and washed water (2×),brine, and passed through a Biotage Phase separator. The mixture wasconcentrated under reduced pressure and the residue was purified onsilica gel using a gradient of 0-10% MeOH in DCM to provide a solid. Thesolid was triturated with ether (3×, sonicating after each addition ofether). The solid was dried over night under reduced pressure at 75° C.to provide 4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide (29mg, 19%): LC/MS (Table 1, Method c) R_(t)=2.34 min; MS m/z 342 (M+H)⁺.(Btk IC₅₀=A)

General Procedure J: Substitution of an Alkyl Halide with an AmineNucleophile

A flask is charged with an alkyl halide (preferably 1 equiv) and anorganic solvent (such as THF, MeCN, DMF, DMA, NMP or DMSO; preferablyTHF or MeCN). To the flask are added in no particular order the aminenucleophile (1 to 25 equiv, preferably 1.2-20 equiv) and an optionally abase (such as LiHMDS, NaH, K₂CO₃, NaHMDS, NaOt-Bu, KHMDS or KOt-Bu,preferably none, NaH or K₂CO₃; 1 to 5 equiv, preferably 1-3 equiv). Themixture is stirred at about 0 to 100° C. (preferably about 0-40° C.) forabout 1 to 24 h (preferably about 3 to 20 h). The mixture may optionallybe concentrated in vacuo to give a residue as the target compound.Either the residue or the solution may be optionally partitioned betweenwater and an organic solvent (such as EtOAc, Et₂O or DCM). The organiclayer is isolated and may optionally be washed in no particular orderwith water and/or aqueous solutions containing an acid (such as HCl,AcOH or NH₄Cl) and/or aqueous solutions containing a base (such asNaHCO₃, Na₂CO₃, NaOH, KOH or NH₄OH) and/or aqueous solutions containingan inorganic salt (such as NaCl Na₂SO₃ or Na₂S₂O₃). The organic solutionmay then be optionally dried with a drying agent (such as anhydrousMgSO₄ or Na₂SO₄), filtered and concentrated in vacuo to give the targetcompound. Alternatively, the residue from concentrating the reactionmixture may be suspended in water, sonicated and collected via vacuumfiltration.

Illustration of General Procedure J Example #J.1:(E)-4-(3-(4-(Dimethylamino)but-2-enamido)-2-methylphenyl)-1H-indole-7-carboxamide

To a solution of(E)-4-(3-(4-bromobut-2-enamido)-2-methylphenyl)-1H-indole-7-carboxamide(1.4 g, 3.40 mmol, prepared using E from4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide (Example #16) and(E)-4-bromobut-2-enoyl chloride [J. Org. Chem. 2011, 76, 4467]) in THF(24 mL) at 0° C. was added 2 M dimethylamine in THF (34.0 mL, 67.9mmol). The mixture was stirred for 3 h while warming to rt. The mixturewas concentrated under reduced pressure and water (15 mL) was added tothe residue. The mixture was sonicated for about 20 min at rt, filtered,washed with water and dried under reduced pressure. The residue wasadded to a silica gel column and was eluted with MeOH/DCM (0-15%) toprovide the crude product (0.650 g). The crude product was dissolved inDMA (5 mL) and water (100 mL) added while stirring for 20 min at rt. Themixture was filtered, washed with water (50 mL×3), and dried underreduced pressure to provide(E)-4-(3-(4-(dimethylamino)but-2-enamido)-2-methylphenyl)-1H-indole-7-carboxamide(0.40 g, 31%): LC/MS (Table 1, Method f) R_(t)=1.05 min; MS m/z 377(M+H)⁺. (Btk IC₅₀ B)

TABLE J.1 Examples prepared from an(E)-4-(3-(4-bromobut-2-enamido)-2-methylphenyl)-1H- indole-7-carboxamide(prepared using E from 4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide (Example #16) and (E)-4-bromobut-2-enoyl chloride[J.Org.Chem. 2011, 76, 4467]) using General Procedure J R_(t) min (Table1, m/z ESI+ Btk Amine Product Example # Method) (M + H)⁺ IC₅₀ piperidine

J.1.1 1.13 (f) 417 B (tetrahydrofuran-2-yl) methanamine

J.1.2 1.13 (f) 433 B 2-methoxyethanamine

J.1.3 1.09 (f) 407 C cyclopropanamine

J.1.4 1.09 (f) 389 B morpholine

J.1.5 1.06 (f) 419 C 1-methylpiperazine

J.1.6 1.14 (f) 432 C

TABLE J.2 Example prepared from(E)-4-(3-(4-bromobut-2-enamido)-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (prepared using E from4-(3-amino-2-methylphenyl)-1H- pyrrolo[2,3-c]pyridine-7-carboxamide(Example #2) and (E)-4-bromobut-2-enoyl chloride [J.Org.Chem. 2011, 76,4467]) using General Procedure J R_(t) min (Table 1, m/z ESI+ Btk AmineProduct Example # Method) (M + H)⁺ IC₅₀ Dimethyl amine

J.2.1 0.70 (g) 378 B

TABLE J.3 Example prepared from cyanic bromide with an amine usingGeneral Procedure J R_(t) min (Table 1, m/z ESI+ Btk Amine ProductExample # Method) (M + H)⁺ IC₅₀ 4-(Azetidin-3- yl(methyl)amino)-2-methyl-1H-indole-7- carboxamide hydrochloride (Prepared using A fromPreparation #40 with methylboronic acid and G with HCl)

J.3.1 1.39 (at) 284 B

General Procedure K: Hydrolysis of an acetonide

To a solution of an acetonide (preferably 1equiv) in an organic solvent(such as 1,4-dioxane and THF, preferably THF) is added an acid, such as4MHCl inl,4-dioxane (3-100 equiv, preferably 30-40 equiv). The reactionmixture is heated at about 20-120° C. (preferably about rt usingconventional heating; about 120° C. using microwave irradiation) forabout 0.25-24 h (preferably about 4 h using conventional heating; about20 min using microwave irradiation). The reaction mixture is allowed tocool to ambient temperature before it is optionally partitioned betweenan organic solvent (such as EtOAc or DCM) and aqueous base (such asNaHCO₃, Na₂CO₃ or NaOH, preferably NaHCO₃) and the aqueous layer isoptionally extracted with additional organic solvent (such as EtOAc orDCM). The organic layer is dried over anhydrous MgSO₄ or Na₂SO₄,filtered, and cond under reduced pressure. Alternatively the solvent isremoved under reduced pressure to give the desired compound.

Illustration of General Procedure K Example#K.1*:2-(1-((R)-2,3-Dihydroxypropyl)-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide

To a solution of2-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(0.047 g, 0.082 mmol, prepared using A from4-bromo-2-iodo-1H-indole-7-carboxamide and(R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Preparation #20), A from3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one[PCT Int. Appl., WO 2011159857]) in THF (5 mL) was added 4 M HCl in1,4-dioxane (0.5 mL). The mixture was stirred at rt for about 4 h. Thereaction mixture was concentrated under reduced pressure and the residuewas purified by prep-HPLC (Table 1, Method af) to provide2-(1-((R)-2,3-dihydroxypropyl)-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide(0.035 g, 80%): LC/MS (Table 1, Method a) R_(t)=1.65 min; MS m/z 535.(Btk IC₅₀=A)

TABLE K.1 Examples prepared from an acetonide using General Procedure KR_(t) min m/z Example (Table 1, ESI+ Btk Acetonide Product # Method)(M + H)⁺ IC₅₀ 2-(1-(((S)-2,2-dimethyl-1,3- dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-4-(2-methyl-3- (4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7- carboxamide (prepared using A from4-bromo-2-iodo-1H- indole-7-carboxamide and Preparation #21, A from 3-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)quinazolin-4(3H)- one [WO 2011159857])

K.1.1 1.64 (a) 535 A

General Procedure L: Hydrogenation of an Alkene

A round bottom flask is charged with a palladium catalyst, such as Pd/Cor Pd(OH)₂ (10 or 20 wt %, about 0.005 to 1.0 equiv, preferably 0.5 to1.0 equiv). The flask is evacuated then flushed with nitrogen 2 to 5times (preferably 3 times) prior to addition of an organic solvent ormixture of solvents (such as EtOAc, MeOH, EtOH or MeOH/AcOH, preferablyMeOH/AcOH) under a nitrogen atmosphere. To the mixture is added analkene (preferably 1 equiv), neat or optionally as a solution in anorganic solvent or mixture of solvents (such as EtOAc, MeOH, EtOH orMeOH/AcOH, preferably MeOH). The mixture is stirred under a hydrogenatmosphere (about 30 to 50 psi) for about 1 to 60 h (preferably about 4to 5 h). Optionally the reaction may be performed using an H-cubeinstrument with either Pd/C or Pd(OH)₂ cartridges (10 or 20 wt %) andthe starting material is passed through the system as a solution in thepreferred solvent/s. In cases where the reaction does not proceed tocompletion as monitored by TLC, LC/MS, or HPLC, the mixture can beoptionally heated to about 30 to 80° C. (preferably about 50° C.) forabout 1 to 24 h (preferably about 16 h) and in cases where the H-cube isused to perform the reaction, the pressure may be increased (25 to 50bar, preferably 40 to 50 bar). The mixture is then filtered and thefilter cake is rinsed with an organic solvent (such as EtOAc, MeOH orEtOH, preferably the reaction solvent) and the filtrate is concentratedunder reduced pressure to give the crude product.

Illustration of General Procedure L Example #L.1:2-(1-Acetylpiperidin-4-yl)-4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide

2-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide(300 mg, 0.772 mmol, prepared using A with4-bromo-2-iodo-1H-indole-7-carboxamide (Preparation #1) and1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone[Combi-Blocks], A with 3-amino-2-methylphenylboronic acid, pinacol ester[Combi-Blocks]) and solvent MeOH (72 mL) were added to 20 wt % Pd/C(60.0 mg, 0.564 mmol) in a 250 mL stainless steel pressure bottle andstirred for about 4.5 h at 30 psi then at about 50° C. for about 16 h.The reaction was filtered, concentrated in vacuo and the residue waspurified on silica gel using a gradient of 0-10% MeOH in DCM to provide2-(1-acetylpiperidin-4-yl)-4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide(77.1 mg, 0.197 mmol): LC/MS (Table 1, Method f) R_(t)=1.06 min; MS m/z391. (Btk IC₅₀=B)

General Procedure M: Removal of a Silyl Group from an O-Silyl Ether

Method 1:

To a solution of an O-silyl-ether (1 equiv) in an organic solvent (suchas DMF, 1,4-dioxane, or DCM, preferably DCM) is added an acid (such asTFA or HCl, 5 to 50 equiv, preferably 30 equiv) and the mixture isstirred at about 0 to 50° C. (preferably about 15 to 25° C.) for about 1to 48 h (preferably about 4 to 16 h). Alternatively, additional acid (5to 20 equiv, preferably 10 equiv) may be added and the mixture is heatedto about 30 to 100° C. (preferably about 50 to 80° C.) for about 0.5 to10 h (preferably about 1 to 5 h).

Method 2:

To a solution of an O-silyl ether (1 equiv) in an organic solvent (suchas DMF, 1,4-dioxane, or DCM, preferably DMF) is added a fluoride sourcesuch as HF, TBAF (1 to 10 equiv, preferably 4 equiv), and the mixture isstirred at about 20 to 110° C. (preferably about 25 to 60° C.) for about1 to 20 h (preferably about 2 to 8 h).

For either method, the targeted compound may optionally be isolated bycooling the mixture and filtering the precipitate. Alternatively, themixture is optionally concentrated in vacuo to give the targetedcompound. Alternatively, the mixture is optionally filtered through amedia (such as silica gel or Celite®) which is rinsed with anappropriate solvent (such as EtOAc, 1,4-dioxane, THF, MeCN, DCM, Et₂O,MeOH, or EtOH) and then optionally concentrated in vacuo to give aresidue. Either the residue or the solution may be optionallypartitioned between water and an organic solvent (such as EtOAc, Et₂O orDCM). The organic layer is isolated and may be optionally washed in noparticular order with water and/or aqueous solutions containing an acid(such as HCl, AcOH or NH₄Cl) and/or aqueous solutions containing a base(such as NaHCO₃, Na₂CO₃, NaOH, KOH or NH₄OH) and/or aqueous solutionscontaining an inorganic salt (such as NaCl, Na₂SO₃ or Na₂S₂O₃). Theorganic solution may then be optionally dried with a drying agent (suchas anhydrous MgSO₄ or Na₂SO₄), filtered and concentrated in vacuo togive the targeted compound.

Illustration of General Procedure M Example #M.1:N-(3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)-2-(hydroxymethyl)phenyl)thiazole-2-carboxamide

To a solution ofN-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)phenyl)thiazole-2-carboxamide(100 mg, 0.170 mmol, prepared using D from thiazole-2-carboxylic acidand2-((tert-butyldimethylsilyloxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline[Matrix], and Preparation #10) in 1,4-dioxane (2 mL) was added 3Naqueous HCl (2 mL, 6.00 mmol) and the mixture was stirred at about 25°C. for about 3 h. The resulting solution was diluted with EtOAc (5 mL)and washed with water (3 mL). The organic phase was dried over Na₂SO₄and concentrated to give a crude product, which was purified by Prep-TLC(DCM:MeOH=20:1) to provideN-(3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4yl)-1H-indol-4-yl)-2-(hydroxymethyl)phenyl)thiazole-2-carboxamide(36 mg, 45): ¹H NMR (DMSO-d6) δ11.16 (s, 1H), 10.92 (s, 1H), 8.32 (s,1H), 8.27-8.25 (d, J=8.4 Hz, 1H), 8.14-8.07 (m, 3H), 7.94 (s, 1H),7.67-7.65 (d, J=6.4 Hz, 1H), 7.46-7.43 (m, 2H), 7.14-7.12 (d, J=7.6 Hz,1H), 6.96-6.94 (d, J=7.6 Hz, 1H), 6.31 (s, 1H), 5.78 (s, 1H), 4.54-4.47(m, 2H), 3.82 (s, 3H). LC/MS (Table 1, Method o) R_(t)=2.73 min; MS m/z:473 (M−H)⁺. (Btk IC₅₀=A)

TABLE M.1 Examples prepared from an O-silyl ether using GeneralProcedure M R_(t) min m/z (Table 1, ESI+ Btk O-silyl ether ProductExample # Method) (M + H)⁺ IC₅₀ 4-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-(6-fluoro-4- oxoquinazolin-3(4H)- yl)phenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H- indole-7-carboxamide (prepared using A fromPreparation #10 and Preparation #11)

M.1.1 3.22 (v) 509 A 4-bromo-2-(1-(2-(tert- butyldimethylsilyloxy)ethyl)-1H-pyrazol-4-yl)-1H- indole-7-carboxamide (prepared using J from4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)- 1H-pyrazole with Awith (2-bromoethoxy)-tert- butyldimethylsilane, 4-bromo-2-iodo-1H-indole-7-carboxamide, A with 3-(2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)quinazolin- 4(3H)-one [WO 2011159857])

M.1.2 1.70 (a) 505 A

General Procedure N: Hydrolysis of a Sulfonamide

To a flask containing a sulfonamide, for example, a sulfonyl-protectedindole, (preferably 1 equiv) in an organic solvent (such as 1,4-dioxane,MeOH, or THF/MeOH, preferably 1,4-dioxane) is added an base (such asK₂CO₃, Cs₂CO₃, aqueous Na₂CO₃ or aqueous NaOH, 1-30 equiv; preferably1-5 equiv for Cs₂CO₃). The mixture is stirred at about 25-100° C.(preferably about 60° C.) for about 1-72 h (preferably about 1-18 h). Incases where the reaction does not proceed to completion as monitored byTLC, LC/MS, or HPLC, additional base (such as K₂CO₃, Cs₂CO₃, aqueousNa₂CO₃ or aqueous NaOH, preferably 1-5 equiv for Cs₂CO₃) and/or acosolvent (such as EtOH) is added. The reaction is continued at about25-100° C. (preferably about 60° C.) for about 0.25-3 h (preferablyabout 1-2 h). In any case where an additional base labile group ispresent (for example, an ester or a cyano group), this group may also behydrolyzed. The reaction is worked up using one of the followingmethods. Method 1. The organic solvent is optionally removed underreduced pressure and the aqueous solution is neutralized with theaddition of a suitable aqueous acid (such as aqueous HCl). A suitableorganic solvent (such as EtOAc or DCM) and water are added, the layersare separated, and the organic solution is dried over anhydrous Na₂SO₄or MgSO₄, filtered, and concentrated to dryness under reduced pressureto give the target compound. Method 2. The organic solvent is optionallyremoved under reduced pressure a suitable organic solvent (such as EtOAcor DCM) and water are added, the layers are separated, and the organicsolution is dried over anhydrous Na₂SO₄ or MgSO₄, filtered, andconcentrated to dryness under reduced pressure to give the targetcompound. Method 3. The reaction mixture is concentrated under reducedpressure and directly purified by one of the subsequent methods.

Illustration of General Procedure N Preparation #N.1:(R)-4-(3-(4-Oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1H-indole-7-carbonitrile

To a mixture of(R)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1-tosyl-1H-indole-7-carbonitrile(0.12 g, 0.229 mmol, prepared using B from4-fluoro-1-tosyl-1H-indole-7-carbonitrile (Preparation #27, step A) and(R)-3-(piperidin-3-yl)quinazolin-4(3H)-one (Preparation #31) in THF (2mL) and MeOH (1 mL) was added cesium carbonate (0.128 mL, 1.60 mmol) andstirred at rt for about 18 h. The reaction was diluted with water (60mL) and stirred for another 20 min. The mixture was extracted into DCM,dried by passing through a Biotage phase separator to remove residualwater and evaporated to dryness to give(R)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1H-indole-7-carbonitrile(0.044 g, 52%); LC/MS (Table 1, Method g) R_(t)=1.50 min.; MS m/z: 370(M+H)⁺

General Procedure O: Hydrolysis of a Nitrile to a Primary Amide

To a flask containing a nitrile, (preferably 1 equiv) in an organicsolvent (such as MeOH, EtOH, DMSO, DMSO/MeOH, or DMSO/EtOH, preferablyDMSO/EtOH) is added a base (such as KOH, aqueous KOH or aqueous NaOH,1-30 equiv, preferably 3-5 equiv for KOH, preferably 10-15 equiv foraqueous NaOH). The mixture is stirred at about rt for about 1-30 min(preferably about 1-10 min) then 30% H₂O₂ (5-30 equiv preferably 9-27equiv) was added to the mixture slowly and the reaction mixture wasstirred at rt for about 10-30 min. In cases where the reaction does notproceed to completion as monitored by TLC, LC/MS, or HPLC, the reactionis continued at rt for about 0.25-1 h (preferably about 0.25-0.5 h). Thereaction is worked up using one of the following methods. Method 1. Themixture is diluted with saturated NH₄Cl and water, stirred at about rtfor about 1-30 min. The resulting suspension is collected by filtration,washed with a suitable solvent (such as MeOH, EtOH, or water), and thefiltercake is dried under vacuum to give the target compound. Method 2.The organic solvent is optionally removed under reduced pressure asuitable organic solvent (such as EtOAc or DCM) and water are added, thelayers are separated, and the organic solution is dried over anhydrousNa₂SO₄ or MgSO₄, filtered, and concentrated to dryness under reducedpressure to give the target compound. Method 3. The reaction mixture isconcentrated under reduced pressure and directly purified by one of thesubsequent methods

Illustration of General Procedure O Example #O.1:N-(trans-1-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-4-hydroxypiperidin-3-yl)thiazole-2-carboxamide

To a stirred solution ofN-(trans-1-(7-cyano-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-4-hydroxypiperidin-3-yl)thiazole-2-carboxamide(36 mg, 0.068 mmol, prepared using B Preparation #27 and Preparation#23, N with Cs₂CO₃) in DMSO (0.8 mL) was added EtOH (4.8 mL) and KOH(12.81 mg, 0.228 mmol). The mixture was stirred at rt for about 10 min,then 30% H₂O₂ (0.070 mg, 0.615 μmol) was added to the mixture slowly andthe reaction mixture was stirred at rt for about 15 min. Then water (6mL) was added to the mixture and the solution was extracted with EtOAc(3×20 mL). The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated to give the crude product which was purifiedby flash chromatography to provideN-(trans-1-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-4-hydroxypiperidin-3-yl)thiazole-2-carboxamide(15 mg, 40%): LC/MS (Table 1, Method d) R_(t)=2.52 min.; MS m/z: 545(M+H)⁺. (Btk IC₅₀=A)

TABLE O.1 Examples prepared using General Procedure O R_(t) min m/zExample (Table 1, ESI+ Btk Nitrile Product # Method) (M + H)⁺ IC₅₀N-(3-(7-cyano-1H-indol-4- yl)-2-methylphenyl)-4-(difluoromethyl)benzamide (prepared using A from 4-bromo-1H-indole-7-carbonitrile and 2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [Combi-Blocks]), N with Cs₂CO₃

O.1.1 1.69 (f) 420 B 4-(2-methyl-3-(oxetan-3- ylamino)phenyl)-1H-indole-7-carbonitrile (prepared using A from 4-bromo-1H-indole-7- carbonitrileand 2-methyl-3-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)aniline[CombiBlocks]), H from oxetan-3-one, N with Cs₂CO₃

O.1.2 1.72 (f) 322 C (R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4- yl)-4-(3-(8-oxo-5,6- dihydroimidazo[1,2-a]pyrazin-7(8H)- yl)piperidin-1-yl)-1H-indole- 7-carbonitrile (preparedusing B from Preparation #27 and Preparation #13, N with Cs₂CO₃

O.1.3* 0.99 (f) 538 A (R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4- yl)-4-(3-(8-oxoimidazo[1,2-a]pyrazin-7(8H)- yl)piperidin-1-yl)-1H-indole- 7-carbonitrile (preparedusing B from Preparation #27 and Preparation #12, N with Cs₂CO₃

O.1.4* 1.18 (f) 536 A (R)-N-(1-(7-cyano-2-(1- (methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H- indol-4-yl)piperidin-3-yl)-2-methyloxazole-4- carboxamide (prepared using B from Preparation #27 and(R)-tert-butyl piperidin-3- ylcarbamate, G with HCl, and D with2-methyloxazole-4- carboxylic acid, N with Cs₂CO₃

O.1.5* 1.43 (f) 527 A (R)-N-(1-(7-cyano-1H-indol-4-yl)piperidin-3-yl)-2- methyloxazole-4- carboxamide (Preparation #V.1),N with Cs₂CO₃

O.1.6* 1.08 (g) 368 (R)-1-(1-(7-cyano-1H-indol- 4-yl)piperidin-3-yl)-3-(thiazol-2-yl)urea (prepared using V with thiazol-2- ylcarbamic acid andPreparation #B.1, N with Cs₂CO₃

O.1.7* 0.72 (g) 385 C (R)-N-(1-(7-cyano-1H-indol-4-yl)piperidin-3-yl)-4- (trifluoromethyl)benzamide (prepared using Vwith 4- (trifluoromethyl)benzoic acid and Preparation #B.1, N withCs₂CO₃

O.1.8* 1.62 (g) 431 C (R)-N-(1-(7-cyano-1H-indol-4-yl)piperidin-3-yl)-4- methoxybenzamide (prepared using V with 4-methoxybenzoic acid and Preparation #B.1, N with Cs₂CO₃

O.1.9* 1.30 (g) 393 C (R)-5-tert-butyl-N-(1-(7- cyano-1H-indol-4-yl)piperidin-3-yl)isoxazole- 3-carboxamide (prepared using V with5-tert- butylisoxazole-3-carboxylic acid and Preparation #B.1, N withCs₂CO₃

O.1.10* 1.70 (g) 410 C (R)-4-(3-aminopiperidin-1-yl)-1H-indole-7-carboxamide (prepared using V with 4-tert-butylbenzoicacid and Preparation #B.1, N with Cs₂CO₃

O.1.11* 1.55 (g) 419 C (R)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1H- indole-7-carbonitrile (Preparation #N.1)

O.1.12* 1.28 (g) 388 C 4-(3-(7-cyclopropyl-5- fluoro-4-oxoquinazolin-3(4H)-yl)piperidin-l-yl)-1H- indole-7-carbonitrile (prepared using Bfrom Preparation #27, step A and Preparation #33, N with Cs₂CO₃

O.1.13 1.63 (g) 446 C (R)-2-(4-fluorophenyl)-4-(3-(4-oxoquinazolin-3(4H)- yl)piperidin-1-yl)-1H-indole- 7-carbonitrile(prepared using A from Preparation #27, step B and 2-(4-fluorophenyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane, B fromPreparation #31, N with Cs₂CO₃

O.1.14* 1.69 (g) 482 B (R)-4-(3-(6-fluoro-4- oxoquinazolin-3(4H)-yl)piperidin-1-yl)-2-(4- fluorophenyl)-1H-indole-7- carbonitrile(prepared using A from Preparation #27, step B and 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane, B from Preparation #32, N withCs₂CO₃

O.1.15* 1.75 (g) 500 C (R)-2-(1-methyl-1H-pyrazol-4-yl)-4-(3-(4-oxoquinazolin- 3(4H)-yl)piperidin-1-yl)-1H-indole-7-carbonitrile (prepared using A from Preparation #27, step B and1-methyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-1H- pyrazole,B from Preparation #31, N with Cs₂CO₃

O.1.16* 1.39 (g) 468 B (R)-4-(3-(6-fluoro-1-oxoisoindolin-2-yl)piperidin- 1-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7- carbonitrile (prepared using A fromPreparation #27, step B and 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole, B from Preparation #30, N with Cs₂CO₃

O.1.18* 1.48 (g) 473 C (R)-4-tert-butyl-N-(1-(7- cyano-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4- yl)piperidin-3-yl)benzamide (prepared using Afrom Preparation #27, step B and 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole, B from (R)-tert- butyl piperidin-3-ylcarbamate, V with 4-tert- butylbenzoic acid, N with Cs₂CO₃

O.1.19* 1.73 (g) 499 A (R)-N-(1-(7-cyano-2-(1-methyl-1H-pyrazol-4-yl)-1H- indol-4-yl)piperidin-3-yl)-4-methoxybenzamide (prepared using A from Preparation #27, step B and1-methyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-1H- pyrazole,B with (R)-tert- butyl piperidin-3- ylcarbamate, V with 4-methoxybenzoic acid, N with Cs₂CO₃

O.1.20* 1.32 (g) 473 B (R)-N-(1-(7-cyano-2-(1-methyl-1H-pyrazol-4-yl)-1H- indol-4-yl)piperidin-3-yl)-4-(trifluoromethyl)benzamide methoxybenzamide (prepared using A fromPreparation #27, step B and 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole, B with (R)-tert- butyl piperidin-3-ylcarbamate, V with 4- (trifluoromethyl)benzoic acid, N with Cs₂CO₃

O.1.21* 1.65 (g) 511 B (R)-N-(1-(7-cyano-2-(1-methyl-1H-pyrazol-4-yl)-1H- indol-4-yl)piperidin-3-yl)-4-(difluoromethyl)benzamide (prepared using A from Preparation #27, step Band 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole, B with (R)-tert- butyl piperidin-3- ylcarbamate, V with 4-(difluoromethyl)benzoic acid, N with Cs₂CO₃

O.1.22* 1.51 (g) 493 B (R)-N-(1-(7-cyano-2-(1-methyl-1H-pyrazol-4-yl)-1H- indol-4-yl)piperidin-3-yl)-4-(2-cyanopropan-2- yl)benzamide (prepared using A from Preparation #27,step B and 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole, B with (R)-tert- butyl piperidin-3-ylcarbamate, V with 4-(1- amino-2-methyl-1- oxopropan-2-yl)benzoic acid,N with Cs₂CO₃

O.1.23* 1.28 (g) 528 B (R)-N-(1-(7-cyano-2-(1-methyl-1H-pyrazol-4-yl)-1H- indol-4-yl)piperidin-3-yl)-4-(trifluoromethoxy)benzamide (prepared using A from Preparation #27, stepB and 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole, B with (R)-tert- butyl piperidin-3- ylcarbamate, V with 4-(trifluoromethoxy)benzoic acid, N with Cs₂CO₃

O.1.24* 1.68 (g) 527 B (R)-N-(1-(7-cyano-2-(1-methyl-1H-pyrazol-4-yl)-1H- indol-4-yl)piperidin-3-yl)-4-cyclopropylbenzamide (prepared using A from Preparation #27, step B and1-methyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)-1H- pyrazole,B with (R)-tert- butyl piperidin-3- ylcarbamate, V with 4-cyclopropylbenzoic acid, N with Cs₂CO₃

O.1.25* 1.40 (g) 483 A (R)-4-tert-butyl-N-(1-(7-cyano-2-(pyridin-3-yl)-1H- indol-4-yl)piperidin-3- yl)benzamide(prepared using A from Preparation #27, step B and pyridin-3- ylboronicacid, B with (R)- tert-butyl piperidin-3- ylcarbamate, V with 4-tert-butylbenzoic acid, N with Cs₂CO₃

O.1.26 1.56 (g) 496 A (R)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-2- (pyridin-3-yl)-1H-indole-7- carbonitrile(prepared using A from Preparation #27, step B and pyridin-3-ylboronicacid with Cs₂CO₃, B from Preparation #31, N with Cs₂CO₃

O.1.27* 1.22 465 B

General Procedure P: Formation of a Boronate from an Aryl Halide orHeteroaryl Halide

To a mixture of an halide, for example, a bromo indole (preferably 1equiv), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1to 3 equiv, preferably 1.2 equiv), potassium acetate (2 to 5 equiv,preferably 3 equiv), and in a solvent (such as THF or 1,4-dioxane;preferably 1,4-dioxane) is added a palladium catalyst (for examplePd₂dba₃ or (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II)complex with DCM; preferably1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) complex withDCM, 0.01 to 0.20 equiv, preferably 0.1 equiv). The mixture is heated atabout 40 to 120° C. (preferably about 80° C.) for about 1 to 24 h(preferably about 16 h). The mixture is allowed to cool to rt and isworked up using one of the following methods. Method 1. The mixture maybe diluted with an organic solvent (such as DCM or EtOAc) and theorganic solution is optionally washed with water and/or brine, driedover anhydrous MgSO₄ or Na₂SO₄, filtered, and the solvent is removedunder reduced pressure to give the desired compound. Method 2. Themixture is concentrated under reduced pressure and optionally purifiedusing one or more of the Purification Methods described above to givethe desired compound. Method 3. The catalyst is removed by filtrationand the filtrate is concentrated under reduced pressure.

Illustration of General Procedure P Preparation #P.1:4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide

A mixture of 4-bromo-1H-indole-7-carboxamide (5 g, 20.9 mmol,Preparation #2),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.37 g,25.1 mmol), potassium acetate (6.16 g, 62.7 mmol) and Pd(dppf)Cl₂-DCM(0.85 g, 1.05 mmol) in 1,4-dioxane (2 mL) was heated at about 80° C.under N₂ overnight. The solvent was removed under reduced pressure toget a residue, which was purified by column chromatography on silica gelto afford4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide(3 g, 50%): ¹H NMR (CDCl₃) δ 10.30 (br, 1H), 7.64-7.62 (d, J=8 Hz, 1H),7.40-7.38 (m, 2H), 7.08-7.07 (m, 1H), 1.42 (s, 12H).

General Procedure Q: Mitsunobu Reaction of an Alcohol

To an alcohol (preferably 1 equiv) in an organic solvent (such as THF,benzene, toluene, or 1,4-dioxane, preferably toluene or 1,4-dioxane) isadded a suitably acidic reactant (such as a carboxylic acid, a phenol ora heteroaryl alcohol, 1-3 equiv, preferably 1 equiv), followed bytri-n-butylphosphine, triphenylphosphine or polymer boundtriphenylphosphine (preferably triphenylphosphine, 1-3 equiv, preferably1.2 equiv), and TMAD, 1,1′-(azodicarbonyl)dipiperidine, DIAD or DEAD(preferably DEAD, 1-3 equiv, preferably 1.2 equiv) is added dropwise atabout 0-120° C. (preferably 0-25° C.). The reaction mixture is stirredat about 25-120° C. for about 5-48 h (preferably about 16 h).Alternatively, after about 0.1-24 h additional phosphine reagent (0.2-2equiv) and TMAD, 1,1′-(azodicarbonyl)dipiperidine, DIAD or DEAD (0.2-1equiv) are added to drive the reaction to completion. Method 1. Whenpolymer bound reagent is used, the reaction mixture is filtered andwashed with a mixture of solvents such as DCM, EtOAc and MeOH(preferably DCM then MeOH). The filtrate is concentrated under reducedpressure. Method 2. When no polymer bound reagent is used, the reactionmixture is optionally diluted with an organic solvent such as DCM orEtOAc and then washed with water, saturated aqueous NaHCO₃, brine anddried over anhydrous Na₂SO₄ or MgSO₄, filtered, and concentrated underreduced pressure. Alternatively, the reaction mixture is directlyconcentrated under reduced pressure.

Illustration of General Procedure Q Preparation #Q.1:2-((4-Bromo-3-nitrophenoxy)methyl)thiazole

To a solution of 4-bromo-3-nitrophenol (2 g, 9.17 mmol, Preparation#S.1), thiazol-2-ylmethanol (1.01 g, 9.17 mmol) and triphenylphosphine(2.9 g, 11.01 mmol) in anhydrous toluene (50 mL) was added DEAD (1.7 mL,11.01 mmol) at about 0° C. under N₂. Then the mixture was heated toreflux overnight. After cooling to rt, the mixture was concentratedunder reduced pressure to give a residue, which was purified by columnchromatography on silica gel to give2-((4-bromo-3-nitrophenoxy)methyl)thiazole (2 g, 69%): ¹H NMR (CDCl₃) δ7.83 (d, J=3.1 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.53 (d, J=3.1 Hz, 1H),7.42 (d, J=3.1 Hz, 1H), 7.12 (dd, J=3.1, 8.8 Hz, 1H), 5.43 (s, 2H).

General Procedure R: Reduction of a Nitro Group to an Amine Using Fe

To a mixture of a nitro-containing compound in a solvent (such as MeOH,EtOH, MeOH/water or EtOH/water, preferably EtOH/water) is added Fe (3 to5 equiv, preferably 5 equiv) and NH₄Cl (3 to 5 equiv, preferably 5equiv). The mixture is heated at about 40 to 100° C. (preferably about80° C.) for about 2 to 24 h (preferably about 16 h). The mixture isallowed to cool to rt and is worked up using one of the followingmethods. Method 1. The mixture may be diluted with an organic solvent(such as DCM or EtOAc) and the organic solution is optionally washedwith water and/or brine, dried over anhydrous MgSO₄ or Na₂SO₄, filtered,and the solvent is removed under reduced pressure to give the desiredcompound. Method 2. The mixture is concentrated under reduced pressureand optionally purified using one or more of the Purification Methodsdescribed above to give the desired compound. Method 3. The catalyst isremoved by filtration and the filtrate is concentrated under reducedpressure. Intermediates and final compounds prepared via this GeneralProcedure can be optionally purified using one or more of thePurification Methods described above.

Illustration of General Procedure R Preparation #R.1:2-Bromo-5-(thiazol-2-ylmethoxy)aniline

To a solution of 2-((4-bromo-3-nitrophenoxy)methyl)thiazole (1 g, 3.2mmol) in EtOH (40 mL) and water (20 mL) was added iron (0.88 g, 15.8mmol) and NH₄Cl (0.85 g, 15.8 mmol). The mixture was heated to refluxovernight. The mixture was filtered and the filtrate was concentratedunder reduced pressure to get a residue, which was diluted by additionof water and extracted by EtOAc. The organic layer was concentratedunder reduced pressure to provide 2-bromo-5-(thiazol-2-ylmethoxy)aniline(0.7 g, 77%): LC/MS (Table 1, Method 1) R_(t)=1.46 min; MS m/z 285(M+H)⁺.

General Procedure S: Demethylation of aryl methyl ether

To a mixture of a methoxy compound in a solvent (such as DCM, DCE, THF,benzene, toluene, or 1,4-dioxane, preferably DCM) is slowly added BBr₃(2 to 24 equiv, preferably 2.5 equiv). The mixture is heated at about 30to 110° C. (preferably about 45° C.) for about 2 to 24 h (preferablyabout 4-24 h). The mixture is allowed to cool to 0-10° C. (preferablyabout 0° C.) and is diluted with water. The mixture may be diluted withan organic solvent (such as DCM or EtOAc) and the organic solution isoptionally washed with water and/or saturated NaHCO₃ and/or brine, driedover anhydrous MgSO₄ or Na₂SO₄, filtered, and the solvent is removedunder reduced pressure to give the desired compound.

Illustration of General Procedure S Preparation #S.1:4-Bromo-3-nitrophenol

To a solution of 1-bromo-4-methoxy-2-nitrobenzene (20 g, 82 mmol) in DCM(800 mL) was added dropwise BBr₃ (19 mL, 207 mmol) in DCM (120 mL). Theresulting mixture was heated to reflux overnight. The mixture was cooledin ice-water and was diluted by addition of water. Then the mixture waswashed with saturated NaHCO₃ and brine. The organic phase was dried overNa₂SO₄, concentrated under reduced pressure to give a residue, which waspurified by column chromatography on silica gel to provide4-bromo-3-nitrophenol (6 g, 31%) as a solid: ¹H NMR (CDCl₃): δ 7.57 (d,J=8.8 Hz, 1H), 7.35 (d, J=2.6 Hz, 1H), 6.94 (dd, J=2.9, 8.6 Hz, 1H),5.90 (br., 1H).

General Procedure T: Buchwald Reaction of an Aryl Halide or a HeteroarylHalide with an Amine

A mixture of an aryl halide or heteroaryl halide (1.0 equiv), an amine(1 to 2.2 equiv, preferably 1 to 1.2 equiv), a palladium catalyst (suchas Pd₂dba₃ or Pd(OAc)₂, preferably Pd₂dba₃; 0.01 to 1.0 equiv,preferably 0.04 to 0.1 equiv), a ligand (such as X-phos, Xanthphos ortert-butyl-X-phos, preferably tert-butyl-X-phos or X-Phos, 0.01 to 2.0equiv, preferably 0.04 to 0.1 equiv) and a base (such as K₂CO₃, Na₂CO₃,Cs₂CO₃, K₃PO₄, NaOt-Bu, KOt-Bu, KOAc, KOH, preferably K₂CO₃; 1 to 5equiv, preferably 1 to 3 equiv) are added to a solvent (such as1,4-dioxane, t-BuOH, preferably t-BuOH). The mixture is degassed underan inert atmosphere (such as nitrogen or argon, preferably nitrogen) andheated with conventional heating at about 80 to 100° C. (preferablyabout 85 to 95° C.) for about 2 to 24 h (preferably about 18 h) or withmicrowave heating at about 100-150° C. for about 30 min to 2 h. Themixture is cooled to rt. The mixture is optionally filtered through amedia (such as silica gel or Celite®) which is rinsed with anappropriate solvent (such as EtOAc, 1,4-dioxane, THF, MeCN, DCM, Et₂O,MeOH, EtOH, DMSO, 1:1 MeOH/DMSO or 2:1 MeOH/DMSO, preferably MeOH/DMSO)and then the filtrate is optionally concentrated in vacuo or under awarm nitrogen stream to give a residue.

Illustration of General Procedure T Preparation #T.1:4-(1-Methyl-1H-pyrazol-5-ylamino)-2-p-tolyl-1H-indole-7-carboxamide

4-Iodo-2-(p-tolyl)-1H-indole-7-carboxamide (99 mg, 0.26 mmol, preparedusing F with 1-(p-tolyl)ethanone), 1-methyl-1H-pyrazol-5-ylamine (27 mg,0.26 mmol, Maybridge-Int), X-Phos (7.53 mg, 0.016 mmol), K₂CO₃ (44 mg,0.316 mmol), and Pd₂dba₃ (14 mg, 0.016 mmol) were combined in t-BuOH(1.32 mL) in a sealed microwaved tube. The tube was degassed and purgedwith N₂ and heated at about 85° C. for 18 h. The reaction was cooled tort and filtered through Celite®. The filtrate was extracted twice withDCM. The combined organic layers were concentrated. The residue productwas purified on a normal phase column (18 mg, 20%): LC/MS (Table 1,Method f) R_(t)=1.48 min; MS m/z 346 (M+H)⁺. (Btk IC₅₀=B)

TABLE T.1 Examples prepared from4-iodo-2-(p-tolyl)-1H-indole-7-carboxamide (prepared using F with1-(p-tolyl)ethanone) using General Procedure T R_(t) min (Table 1, m/zESI+ Btk Amine Product Example # Method) (M + H)⁺ IC₅₀1-(4-methoxybenzyl)-1H- pyrazo1-5-amine

T.1.1 1.77 (f) 452 B

General Procedure U: Negishi Cross-Coupling Reaction of an Aryl Halideor a Heteroaryl Halide

with an Organozinc A mixture of an aryl halide or heteroaryl halide(preferably 1.0 equiv) an organic solvent or mixture of solvents (suchas THF, Et₂O or 1,4-dioxane, preferably THF), an organozinc compound(0.67 to 1.5 equiv, preferably 0.9 to 1.2 equiv), a palladium catalyst(such as Pd(PPh₃)₄, 0.01 to 1.0 equiv, preferably 0.025 to 0.10 equiv)is stirred at about rt to 90° C. (preferably about 85° C.) for about 1to 24 h (preferably about 18 h). The mixture is cooled to rt. Themixture is optionally filtered through a media (such as silica gel orCelite®) which is rinsed with an appropriate solvent (such as EtOAc,1,4-dioxane, THF, MeCN, DCM, Et₂O, MeOH, EtOH) and then optionallyconcentrated in vacuo to give a residue. Either the residue or thesolution may be optionally partitioned between water and an organicsolvent (such as EtOAc, Et₂O or DCM). The organic layer is isolated andmay be optionally washed in no particular order with water and/oraqueous solutions containing an acid (such as HCl, AcOH or NH₄Cl) and/oraqueous solutions containing a base (such as NaHCO₃, Na₂CO₃, NaOH, KOHor NH₄OH) and/or aqueous solutions containing an inorganic salt (such asNaCl, Na₂SO₃ or Na₂S₂O₃). The organic solution may then be optionallydried with a drying agent (such as anhydrous MgSO₄ or Na₂SO₄), filteredand concentrated in vacuo to give the targeted compound.

Illustration of General Procedure U Preparation #U.1:4-(2-Chloro-6-fluorobenzyl)-2-p-tolyl-1H-indole-7-carboxamide

4-Iodo-2-(p-tolyl)-1H-indole-7-carboxamide (97 mg, 0.258 mmol, preparedusing F from 1-(p-tolyl)ethanone), (2-chloro-6-fluorobenzyl)zinc(II)bromide (0.77 mL, 0.387 mmol) andtetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) weredissolved in THF (0.82 mL) in a sealed microwave tube and heatedthermally at 85° C. for about 18 h. The reaction was cooled to rt andfiltered through Celite®. The filtrate was concentrated to give aresidue. The residue was purified on a normal phase column eluting withEtOAc in hexane to give4-(2-chloro-6-fluorobenzyl)-2-p-tolyl-1H-indole-7-carboxamide (30 mg,30%): LC/MS (Table 1, Method f) R_(t)=2.09 min; MS m/z 393 (M+H)⁺.

TABLE U.1 Examples prepared from4-iodo-2-(p-tolyl)-1H-indole-7-carboxamide (prepared using F with1-(p-tolyl)ethanone) using General Procedure U R_(t) min (Table 1, m/zESI+ Organozinc Product Example # Method) (M + H)⁺ Btk IC₅₀(2,6-dichlorobenzyl)zinc(II) bromide

U.1.1 2.13 (f) 409 C 2-Thiazolylzinc bromide

U.1.2 1.76 (f) 334 A 2-Pyridylzinc bromide

U.1.3 1.34 (g) 328 B

General Procedure V: Formation of an Amide from a Boc-Protected Amineand a Carboxylic Acid

To a solution of an N-Boc amine (1 equiv) in an organic solvent (such asDCM, DCE, 1,4-dioxane or MeOH, preferably DCM or 1,4-dioxane) is addedan acid (such as TFA or HCl, preferably TFA; 2 to 100 equiv, preferably25 to 50 equiv). The mixture is stirred at about 0 to 100° C.(preferably about 20 to 60° C.) for about 0.5 to 24 h (preferably about0.5 to 6 h). Optionally, additional acid (2 to 35 equiv, preferably 20to 25 equiv) may be added and the mixture stirred at about 0 to 100° C.(preferably about 20 to 60° C.) for about 1 to 24 h (preferably about 1to 6 h). If a solid is present in the mixture, the mixture may beoptionally filtered and the solid washed with an organic solvent such as1,4-dioxane or Et₂O. The resulting solid is then optionally dried underreduced pressure. Alternatively, the reaction miture is concentratedunder reduced pressure. To the residue in a flask is added in noparticular order, a carboxylic acid or carboxylate salt (1 to 5 equiv,preferably 1.1 to 1.5 equiv) an organic solvent (such as DCM, DCE, DMF,THF, or 1,4-dioxane, preferably DCM or DMF), a peptide coupling reagent(such as BOP-Cl, IBCF, HATU, DCI, PyBOP, or EDCHCl, preferably HATU; 1to 10 equiv, preferably 1 to 2 equiv), a base (such as TEA, DIEA,pyridine or DIEA, preferably DIEA; 1 to 20 equiv, preferably 1 to 5equiv) and optionally HOBt (0 to 5 equiv, preferably 0 to 1 equiv). Themixture is then stirred at about 10 to 60° C. (preferably about 25 to50° C.) for about 15 min to 48 h (preferably about 15 min to 24 h).Optionally, additional amounts of the reagents above can be added todrive the reaction to completion. The mixture is optionally concentratedin vacuo to give the targeted compound. The mixture is optionallyfiltered through a media (such as silica gel or Celite©) which is rinsedwith an appropriate solvent (such as EtOAc, 1,4-dioxane, THF, MeCN, DCM,Et₂O, MeOH, EtOH) and then optionally concentrated in vacuo to give aresidue. Either the residue or the solution may be optionallypartitioned between water and an organic solvent (such as EtOAc, Et₂O orDCM). The organic layer is isolated and may be optionally washed in noparticular order with water and/or aqueous solutions containing an acid(such as HCl, AcOH or NH₄Cl) and/or aqueous solutions containing a base(such as NaHCO₃, Na₂CO₃, NaOH, KOH or NH₄OH) and/or aqueous solutionscontaining an inorganic salt (such as NaCl, Na₂SO₃ or Na₂S₂O₃). Theorganic solution may then be optionally dried with a drying agent (suchas anhydrous MgSO₄ or Na₂SO₄), filtered and concentrated in vacuo togive the targeted compound.

Illustration of General Procedure V Preparation #V.1:(R)—N-(1-(7-cyano-1H-indol-4-yl)piperidin-3-yl)-2-methyloxazole-4-carboxamide

To a solution of (R)-tert-butyl1-(7-cyano-1H-indol-4-yl)piperidin-3-ylcarbamate (0.11 g, 0.333 mmol,Preparation #B.1) in DCM (1 mL) was added TFA (1 mL) and the solutionstirred at about 25° C. for about 30 min. The mixture was evaporated todryness followed by the addition of DMF (2 mL), TEA (0.139 mL, 0.999mmol), HATU (190 mg, 0.499 mmol) and 2-methyloxazole-4-carboxylic acid(0.055 g, 0.433 mmol) The mixture was stirred at about rt for about 18h. The reaction was evaporated and the resulting residue was purified bysilica gel chromatography eluting with a gradient of 30-100% EtOAc inhexane to(R)—N-(1-(7-cyano-1H-indol-4-yl)piperidin-3-yl)-2-methyloxazole-4-carboxamide(0.092 g, 79%); LC/MS (Table 1, Method g)₁4=1.35 min.; MS m/z: 350(M+H)⁺

General Procedure W: Conversion of a Vinyl Triflate to a Vinyl Boronateor Boronic Acid

To a mixture of a boronic acid or boronate (1 to 2 equiv, preferably 1.1equiv) a palladium catalyst (for example Pd(OAc)₂, Pd₂dba₃, Pd(PPh₃)₄,bis(acetato)triphenylphosphinepalladium(II), PdCl2 (dppf),(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II), orPd(PPh₃)₂Cl₂; preferably PdCl₂(dppf) or Pd(PPh₃)₂Cl₂; 0.01 to 0.20equiv, preferably 0.05 to 0.1 equiv), abase (such as KF, KOAc, Na₂CO₃,K₂CO₃ or Cs₂CO₃, preferably K₂CO₃ or KOAc) (1.1 to 16 equiv, preferably1.5 to 2 equiv) and optionally a phosphine additive (preferably PPh₃;0.01 to 0.1 equiv, preferable 0.06 equiv) in an organic solvent (such asdioxane, DME or DCE, preferably dioxane) is added a vinyl triflate (1equiv). The mixture is heated under inert atmosphere at about 60 to 90°C. (preferably 70 to 80° C.) for about 1 to 20 h (preferably 8 to 16 h).The mixture is optionally concentrated in vacuo to give the targetedcompound. Alternatively, the mixture is optionally filtered through amedia (such as silica gel or Celite®) which is rinsed with anappropriate solvent (such as EtOAc, 1,4-dioxane, THF, ACN, DCM, Et₂O,MeOH, or EtOH) and then optionally concentrated in vacuo to give aresidue. Either the residue or the solution may be optionallypartitioned between water and an organic solvent (such as EtOAc, Et₂O orDCM). The organic layer is isolated and may be optionally washed in noparticular order with water and/or aqueous solutions containing an acid(such as HCl, AcOH or NH₄Cl) and/or aqueous solutions containing a base(such as NaHCO₃, Na₂CO₃, NaOH, KOH or NH₄OH) and/or aqueous solutionscontaining an inorganic salt (such as NaCl, Na₂SO₃ or Na₂S₂O₃). Theorganic solution may then be optionally dried with a drying agent (suchas anhydrous MgSO₄ or Na₂SO₄), filtered and concentrated in vacuo togive the targeted compound.

Illustration of General Procedure W Preparation #W.1: tert-Butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate

A 100 mL 3 neck round-bottomed flask was charged with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.10 g,4.34 mmol, Preparation #AA.1), PPh₃ (0.062 g, 0.24 mmol), Pd(PPh₃)₂Cl₂(0.138 g, 0.197 mmol) and K₂CO₃ (0.818 g, 5.92 mmol). To this mixturewas added a solution of tert-butyl6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate(1.37 g, 3.94 mmol) in dioxane (30 mL). The entire mixture was degassedfor about 5 min and purged with nitrogen. The mixture was heated atabout 75° C. for about 15 h. The mixture was diluted with EtOAc (30 mL)and water (30 mL). The organic layer was separated, dried over MgSO₄,filtered and concentrated. The resulting mixture was purified silica gelchromatography (10-40% EtOAc/heptane) to give tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate(0.57 g, 44%): LC/MS (Table 1, Method as) R_(t)=2.65 min; MS m/z: 226(M+H-Boc)+

General Procedure X: Hydrolysis of an Ester to a Carboxylic Acid UnderBasic Conditions and Removal of a Tosyl Group from an N-Tosyl ProtectedHeteroaryl Ring

To a flask containing a compound with and ester functionality and atosyl-protected heteroaromatic ring (1 equiv) either neat or in anorganic solvent (such as 1,4-dioxane, MeOH, or THF/MeOH, THF/water/MeOHpreferably THF/water/MeOH) is added a base or combination of bases (suchas aqueous or solid Na₂CO₃, KOH, Cs₂CO₃, K₂CO₃, NaOH or LiOH, preferablyLiOH, or KOH; 1 to 10 equiv, preferably 5 to 10 equiv). The mixture isstirred at about 0 to 100° C. (preferably about 40 to 85° C.) for about1 to 48 h (preferably about 1 to 24 h). Optionally, more base is added(such as aqueous or solid Na₂CO₃, KOH, Cs₂CO₃, K₂CO₃, NaOH or LiOH,preferably LiOH or NaOH, 1 to 10 equiv, preferably 2 to 6 equiv) and themixture is stirred at about 0 to 100° C. (preferably about 10 to 100°C.) for about 1 to 48 h (preferably about 4 to 24 h). The mixture isthen acidified with the addition of a suitable aqueous acid (such asaqueous HCl, AcOH or citric acid, preferably citric acid). The mixtureis optionally concentrated in vacuo to give the targeted compound.Alternatively, the mixture is optionally filtered through a media (suchas silica gel or Celite®) which is rinsed with an appropriate solvent(such as EtOAc, 1,4-dioxane, THF, ACN, DCM, Et₂O, MeOH, or EtOH) andthen optionally concentrated in vacuo to give a residue. Either theresidue or the solution may be optionally partitioned between water andan organic solvent (such as EtOAc, Et₂O or DCM). The organic layer isisolated and may be optionally washed in no particular order with waterand/or aqueous solutions containing an acid (such as HCl, AcOH or NH₄Cl)and/or aqueous solutions containing a base (such as NaHCO₃, Na₂CO₃,NaOH, KOH or NH₄OH) and/or aqueous solutions containing an inorganicsalt (such as NaCl, Na₂SO₃ or Na₂S₂O₃). The organic solution may then beoptionally dried with a drying agent (such as anhydrous MgSO₄ orNa₂SO₄), filtered and concentrated in vacuo to give the targetedcompound.

Illustration of General Procedure X Preparation #X.1:4-(1-(tert-Butoxycarbonyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1H-indole-7-carboxylicacid

A round bottom flask was charged with methyl4-(1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1-tosyl-1H-indole-7-carboxylate(1.67 g, 2.30 mmol, Preparation #39) in THF (12 mL), water (4 mL) andMeOH (4 mL). LiOH (monohydrate, 0.468 g, 11.1 mmol) was added. Themixture was stirred at about 60° C. After about 7 h additional LiOH(monohydrate, 0. 234 g, 5.57 mmol) was added and the mixture was allowedto stir for about 24 h at about 60° C. The mixture was diluted with 5%citric acid (200 mL) and extracted with DCM (2×100 mL) and 3:1, CHCl₃:isopropanol (100 mL). The combined organic layers were washed with water(50 mL) and dried over Na₂SO₄, filtered and concentrated under reducedpressure to give4-(1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-methyl-1H-indole-7-carboxylicacid (1.16 g, 93%): LC/MS (Table 1, Method as) R_(t)=2.33 min; MS m/z:355 (M−H)⁻.

General Procedure Y: Iodination of a 1H-indole or a 1H-aza indole ringto give a 2-iodo-1H-indole or a 2-iodo-1H-azaindole ring

To a solution of an indole or azaindole (1 equiv) in an organic solvent(such as THF or Et₂O, preferably THF) at about −60 to −78° C.(preferably about −70 to −78° C.) is added a base (such as BuLi or LDA,preferably LDA; 1 to 2 equiv, preferably 1.1 to 1.5 equiv). The reactionmixture is then stirred for about 30 to 45 min and iodine (1 to 2 equiv,preferably 1.4 to 1.6 equiv) is then added. The reaction mixture isstirred for about 10 to 60 min (preferably about 10 to 30 min). Themixture is optionally quenched with Na₂S₂O₃. The mixture is optionallyconcentrated in vacuo to give the targeted compound. Either the residueor the solution may be optionally partitioned between water and anorganic solvent (such as EtOAc, Et₂O or DCM). The organic layer isisolated and may be optionally washed in no particular order with waterand/or aqueous solutions containing an acid (such as HCl, AcOH or NH₄Cl)and/or aqueous solutions containing a base (such as NaHCO₃, Na₂CO₃,NaOH, KOH or NH₄OH) and/or aqueous solutions containing an inorganicsalt (such as NaCl, Na₂SO₃ or Na₂S₂O₃). The organic solution may then beoptionally dried with a drying agent (such as anhydrous MgSO₄ orNa₂SO₄), filtered and concentrated in vacuo to give the targetedcompound.

Illustration of General Procedure Y Preparation #Y.1: 1-tert-Butyl7-methyl4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-iodo-1H-indole-1,7-dicarboxylate

A solution of anhydrous 1-tert-butyl 7-methyl4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-indole-1,7-dicarboxylate(10.0 g, 22.5 mmol, (Preparation #Z.1) in THF (136 mL) was cooled toabout −78° C. and LDA (1M in THF, 33.7 mL, 33.7 mmol) was added dropwise. After about 45 min, a solution of iodine (7.99 g, 31.5 mmol) inTHF (15 mL) was added drop wise while maintaining the temperature atabout −71° C. The reaction mixture was then quenched by pouring into anaqueous solution of Na₂S₂O₃ and NaHCO₃ (10:1, 150 mL). The mixture wasdiluted with EtOAc and the layers were separated. The aqueous phase wasextracted with EtOAc (3×50 mL). The combined organic layers were washedwith brine, dried over MgSO4 and filtered. The solvent was removed underreduced pressure to give methyl4-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole-7-carboxylate(10.4 g, 97%): LC/MS (Table 1, Method as) R_(t)=2.90 min; MS m/z: 588(M+NH₄)⁺.

General Procedure Z: Formation of an N-Boc Protected Amine

To a solution of an amine or amine salt (preferably 1 equiv) in anorganic solvent (such as ACN, 1,4-dioxane, DCM, DMF or THF, preferablyDCM) is added an aqueous base such as Na₂CO₃, NaOH, K₂CO₃ or NaHCO₃,preferably Na₂CO₃ (2 to 20 equiv, preferably 2 to 10 equiv) or anorganic base such as TEA or DIEA, preferably TEA (1 to 5 equiv,preferably 1 to 2 equiv) followed by addition of a Boc transfer reagentsuch as BoC₂O, Boc ON, Boc-azide or Boc-OSu preferably Boc₂O (1 to 4equiv, preferably 1 to 2 equiv). Optionally, an additive, such as DMAP(0.01 to 0.1 equiv, preferable 0.05 equiv) may be added. The addition ofbase is optional if an amine salt is not used. The mixture is stirred atabout 0 to 40° C. (preferably about 0 to 25° C.) for about 2 to 24 h(preferably about 2 to 16 h). The mixture may optionally be concentratedin vacuo to give the target compound. Alternatively, the mixture isoptionally filtered through a media (such as silica gel or Celite®)which is rinsed with an appropriate solvent (such as EtOAc, 1,4-dioxane,THF, ACN, DCM, Et₂O, MeOH, EtOH) and then optionally concentrated invacuo to give a residue as the target compound. Either the residue orthe solution may be optionally partitioned between water and an organicsolvent (such as EtOAc, Et₂O or DCM). The organic layer is isolated andmay optionally be washed in no particular order with water and/oraqueous solutions containing an acid (such as HCl, AcOH or NH₄Cl) and/oraqueous solutions containing a base (such as NaHCO₃, Na₂CO₃, NaOH, KOHor NH₄OH) and/or aqueous solutions containing an inorganic salt (such asNaCl Na₂SO₃ or Na₂S₂O₃). The organic solution may then be optionallydried with a drying agent (such as anhydrous MgSO₄ or Na₂SO₄), filteredand concentrated in vacuo to give the target compound.

Illustration of General Procedure Z Preparation #Z.1: 1-tert-Butyl7-methyl4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-indole-1,7-dicarboxylate

In a 200 mL round-bottomed flask, methyl4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-indole-7-carboxylate (12.4g, 36.0 mmol, prepared using A from methyl4-bromo-1H-indole-7-carboxylate [Anthem] with tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate[AKSCI] and L with Pd/C) and di-tert-butyl dicarbonate (9.43 g, 43.2mmol)) in ACN (100 mL) were added. DMAP (0.22 g, 1.8 mmol) was added,the reaction mixture was stirred at rt for about 18 h, TEA (10 mL, 72mmol) and di-tert-butyl dicarbonate (1.60 mL, 6.87 mmol) were added. Thereaction mixture was stirred at rt for about 16 h. The mixture wasextracted with dilute acetic acid and EtOAc. The combined organic layerswere dried over MgSO4, concentrated under reduced pressure and purifiedusing silica gel chromatography (0-25% EtOAC/heptane) to give1-tert-butyl 7-methyl4-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-1H-indole-,7-dicarboxylate(12.5 g, 70%, 89% purity): LC/MS (Table 1, Method as) R_(t)=2.79 min; MSm/z: 462 (M+NH₄).

General Procedure AA: Conversion of a Cyclic Ketone to a Cyclic VinylTriflate

A solution of a ketone (1 equiv) in an organic solvent (such as THF,dioxane or ether preferably THF) is cooled to about −60 to −78° C.(preferably about −65 to −75° C.). A base is then added slowly (such asLiHMDS, KHMDS or NaHMDS preferably KHMDS). After about 20 to 60 min(preferably 60 min) a solution of a triflating reagent is added, suchas, N-(5-Chloro-2-pyridyl)bis(trifluoromethanesulfonimide)) or1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamidein THF. The reaction mixture is then allowed to warm to rt over about 1to 1.5 h. The reaction mixture may then be quenched with a saturatedsolution of NH₄Cl or water and diluted with an organic solvent (such asDCM or EtOAc). The layers are separated, the organic solution isoptionally washed with water and/or brine, dried over anhydrous MgSO₄ orNa₂SO₄, filtered, and the solvent is removed under reduced pressure togive the desired compound.

Illustration of General Procedure AA Preparation #AA.1: tert-Butyl6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate

To a solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (5.00 g,23.2 mmol) [Arkpharm] in THF (51.6 mL) at about −78° C. was added KHMDS(1M in THF, 30.2 mL, 30.2 mmol) drop wise maintaining internaltemperature of about −72 to −74° C. The mixture was then stirred atabout −77° C. for about 1 h. A solution of1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(7.88 g, 22.1 mmol) in THF (25.8 mL) was added drop wise. The mixturewas gradually warmed to about 0° C. over about 1 to 2 h. The reactionmixture was quenched with a saturated aqueous solution of NH₄Cl andextracted with EtOAc (2×75 mL). The combined organic layers were washedwith brine, dried over MgSO₄, filtered, concentrated under reducedpressure and passed through a plug of neutral alumina (EtOAc/heptane aseluent) to yield(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate(5.1 g, 63.2%); ¹H NMR (400 MHz, DMSO-d₆) δ 7.17 (s, 1H), 4.41 (s, 2H),3.77 (q, J=2.3 Hz, 4H), 1.45 (s, 9H).

General Procedure AB: Reduction of a Double Bond and Removal of a CBZGroup from a CBZ Protected Amine

A round bottom flask is charged with a palladium catalyst, such as Pd/Cor Pd(OH)₂ (10 or 20 wt %, about 0.005 to 1.0 equiv, preferably 0.5 to1.0 equiv). The flask is evacuated then flushed with nitrogen 2 to 5times (preferably 3 times) prior to addition of an organic solvent ormixture of solvents (such as EtOAc, MeOH, EtOH or MeOH/AcOH, preferablyMeOH/AcOH) under a nitrogen atmosphere. To the mixture is added acompound with an alkene functionality and an N-CBZ protected amine(preferably 1 equiv), neat or optionally as a solution in an organicsolvent or mixture of solvents (such as EtOAc, MeOH, EtOH or MeOH/AcOH,preferably MeOH). The mixture is stirred under a hydrogen atmosphere(about 30 to 50 psi) for about 1 to 60 h (preferably about 4 to 5 h).Optionally the reaction may be performed using an H-cube instrument witheither Pd/C or Pd(OH)₂ cartridges (10 or 20 wt %) and the startingmaterial is passed through the system as a solution in the preferredsolvent/s. In cases where the reaction does not proceed to completion asmonitored by TLC, LC/MS, or HPLC, the mixture can be optionally heatedto about 30 to 80° C. (preferably about 50° C.) for about 1 to 24 h(preferably about 16 h) and in cases where the H-cube is used to performthe reaction, the pressure may be increased (25 to 50 bar, preferably 40to 50 bar). The mixture is then filtered and the filter cake is rinsedwith an organic solvent (such as EtOAc, MeOH or EtOH, preferably thereaction solvent) and the filtrate is concentrated under reducedpressure to give the crude product.

Illustration of General Procedure AB Preparation#AB.1:4-(Piperidin-3-yl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide

A round bottom flask was charged with Pd(OH)₂ (20 wt %, 0.336 g, 0.478mmol) followed by the slow addition of a solution of benzyl3-(7-carbamoyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate(1.8 g, 4.8 mmol, prepared using A from Preparation #45 and benzyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate[Arkpharm], Y with LiOH and D with NH₄Cl) in MeOH (30 mL) and AcOH (10mL). The flask was purged with N₂, then filled with H₂ using a balloon.The reaction mixture was then heated at about 45° C. for about 3 h. Thereaction mixture was cooled to rt and filtered through a pad of Celite©,washing with MeOH. The filtrate was concentrated under reduced pressure,dissolved in MeOH and then treated with MP-carbonate beads by stirringat rt for about 2 h. The beads were filtered off and the filtrate wasconcentrated under reduced pressure to give4-(piperidin-3-yl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide (0.84 g,72%): LC/MS (Table 1, Method as) R_(t)=0.58 min.; MS m/z: 245 (M+H)⁺.

General Procedure AC: N-Oxidation of an N Containing Hetero AromaticRing

A solution of an N-containing hetero aromatic compound (1 equiv) in anorganic solvent (such as DCE, DME, DCM or EtOAc, preferably DCM) iscooled to about 0° C. and an oxidizing reagent such as3-chlorobenzoperoxoic acid or magnesium monoperoxyphthalate hexahydrate(1 to 3 equiv, preferably 2 equiv). The solution is stirred at rt forabout 2 to 24 h (preferably about 10 to 16 h). The mixture is optionallyfiltered to give the desired product or optionally concentrated in vacuoto give a residue, either the residue or the solution may be optionallypartitioned between water and an organic solvent (such as EtOAc, Et₂O orDCM). The organic layer is isolated and may optionally be washed in noparticular order with water and/or aqueous solutions containing an acid(such as HCl, AcOH or NH₄Cl) and/or aqueous solutions containing a base(such as NaHCO₃, Na₂CO₃, NaOH, KOH or NH₄OH) and/or aqueous solutionscontaining an inorganic salt (such as NaCl Na₂SO₃ or Na₂S₂O₃). Theorganic solution may then be optionally dried with a drying agent (suchas anhydrous MgSO₄ or Na₂SO₄), filtered and concentrated in vacuo togive the target compound.

Illustration of General Procedure AC Preparation #AC.1:4-Bromo-1H-pyrrolo[2,3-c]pyridine 6-oxide

A flask was charged with 4-bromo-1H-pyrrolo[2,3-c]pyridine (10.0 g, 50.8mmol) [Combiblocks] and dissolved in EtOAc (254 mL). The flask wascooled to about 0° C. and a solution of 3-chlorobenzoperoxoic acid (10.5g, 60.9 mmol) in EtOAc (254 mL) was slowly added. The reaction wasstirred warming to rt for about 16 h. The precipitate that had formedwas collected via filtration and dried in vacuum oven to afford4-bromo-1H-pyrrolo[2, 3-c]pyridine 6-oxide (0.85 g, 79%): LC/MS (Table1, Method as) R_(t)=1.18 min; MS m/z: 213, 215 (M+H)⁺.

General Procedure AD: Cyanation of an N-Oxide Containing Heteroaryl Ring

A flask is charged with an N-oxide heteroaromatic compound (1 equiv) inan appropriate organic solvent, such as ACN. TEA is added (1 to 2 equiv,preferably 1.5 equiv). TMSCN (2 to 5 equiv, preferable 3 to 4 equiv) isthen added using a syringe. The reaction mixture is refluxed untilcomplete consumption of starting material is observed either via TLC orLC/MS. The reaction mixture is cooled to rt and quenched appropriately,preferable with an aqueous solution of NaOH and extracted with anorganic solvent, such as DCM or EtOAC. The organic layer is isolated andmay optionally be washed in no particular order with water and/oraqueous solutions containing an acid (such as HCl, AcOH or NH₄Cl) and/oraqueous solutions containing a base (such as NaHCO₃, Na₂CO₃, NaOH, KOHor NH₄OH) and/or aqueous solutions containing an inorganic salt (such asNaCl Na₂SO₃ or Na₂S₂O₃). The organic solution may then be optionallydried with a drying agent (such as anhydrous MgSO₄ or Na₂SO₄), filteredand concentrated in vacuo to give the target compound.

Illustration of General Procedure AD Preparation #AD.1:4-Bromo-1H-pyrrolo[2,3-c]pyridine-7-carbonitrile

A flask was charged with 4-bromo-1H-pyrrolo[2,3-c]pyridine-6-oxide3-chlorobenzoate (6.25 g, 16.91 mmol, Preparation #AC.1) in ACN (97 mL)and TEA (3.56 mL, 25.4 mmol). TMSCN (9.02 mL, 67.6 mmol) was added inone portion via syringe the mixture was refluxed for about 45 min. Thereaction was quenched by careful addition of 50 mL of aqueous 1 M NaOHsolution, transferred to a separatory funnel and diluted with aqueous 1MNaOH solution (200 mL) and EtOAc (200 mL). The layers were separated andthe organic phase was washed again with 50 mL of aqueous 1 M NaOHsolution. The combined aqueous extracts were washed with EtOAc (4×75 mL)and then with 1 M NaOH (2×20 mL) and brine (1×50 mL), dried over Na₂SO₄,filtered and the solvent was removed to afford4-bromo-1H-pyrrolo[2,3-c]pyridine-7-carbonitrile (3.84 g, 93%): ¹H NMR(400 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.90 (d, J=2.8 Hz, 1H), 6.60 (d,J=2.8 Hz, 1H).

General Procedure AE: Reduction of an Ester to Form an Alcohol

To a solution of an ester in an appropriate organic solvent (such asTHF, dioxane, DCM or EtOAc, preferably THF) is optionally added water (1to 4 equiv, preferably 2 equiv). The mixture is then cooled to about 0°C. and a reducing agent is added (such as LiBH₄ or LAH, preferablyLiBH₄; 2 to 12 equiv, preferably 6 equiv). The reaction mixture isstirred for about 5 to 24 h until complete consumption of the ester.Additional reducing agent may be optionally added as required. Thereaction mixture is then quenched with an aqueous solution of NH₄C. Theorganic layer is isolated and may optionally be washed in no particularorder with water and/or aqueous solutions containing an acid (such asHCl, AcOH or NH₄Cl) and/or aqueous solutions containing a base (such asNaHCO₃, Na₂CO₃, NaOH, KOH or NH₄OH) and/or aqueous solutions containingan inorganic salt (such as NaCl Na₂SO₃ or Na₂S₂O₃). The organic solutionmay then be optionally dried with a drying agent (such as anhydrousMgSO₄ or Na₂SO₄), filtered and concentrated in vacuo to give the targetcompound.

Illustration of General Procedure AE Preparation #AE.1: tert-Butyl3-(7-carbamoyl-1H-indol-4-yl)-5-(hydroxymethyl)piperidine-1-carboxylate

In a 500 mL round-bottomed flask, 1-tert-butyl 3-methyl5-(7-carbamoyl-1H-indol-4-yl)piperidine-1,3-dicarboxylate (6.75 g, 16.8mmol, prepared using Z from Preparation #AF.1) in THF (150 mL) wasadded. The reaction mixture was cooled to about 0° C. and water (0.606mL, 33.6 mmol) was added. LiBH₄ (2.93 g, 135 mmol) was added andreaction mixture stirred at rt for about 12 h. Additional LiBH₄ (2.93 g,135 mmol) was added and reaction mixture was stirred for about 3 h. Thereaction mixture was carefully added to a saturated aqueous solution ofNH₄Cl (800 mL) at about −10° C. The mixture was extracted with DCM (500mL). The DCM layer was dried over MgSO₄, filtered and concentrated togive crude tert-butyl3-(7-carbamoyl-1H-indol-4-yl)-5-(hydroxymethyl)piperidine-1-carboxylate(6.35 g, 101%): LC/MS (Table 1, Method as) R_(t)=1.74 min; MS m/z: 374(M+H)⁺.

General Procedure AF: Reduction of a Pyridine Ring to a Piperiding Ring

To a solution of the pyridine (1 equiv) in acetic acid is added areducing reagent (such as PtO₂, Pd(OH)₂ or Pd/C, preferably PtO₂; 0.05to 0.5 equiv, preferable 0.1 to 0.2 equiv). The reaction mixture isheated at about 50° C. at about 20 to 50 psi (preferably about 30 psi)for about 6 to 12 h (preferably about 10 h). The reaction mixture isconcentrated under reduced pressure to give the desired compound.

Illustration of General Procedure AF Preparation #AF.1: Methyl5-(7-carbamoyl-1H-indol-4-yl)piperidine-3-carboxylate

Methyl 5-(7-carbamoyl-1H-indol-4-yl)nicotinate (6.25 g, 23.7 mmol,prepared using A from Preparation #P.1 with methyl 5-bromonicotinate)and AcOH (70 mL) were added to PtO₂ (1.26 g, 5.55 mmol) in a 50 mLpressure bottle and shaken for about 10 h at about 50° C. at about 30psi. The resulting black solution was concentrated under reducedpressure and filtered through a plug of Celite® and washed with DCM. Thefiltrate was then concentrated to a thick viscous black oily residue.This material was dissolved in 15% MeOH/EtOAc and passed through a largesilica gel plug. The plug was flushed with 10% MeOH/EtOAc (250 mL), then35-40% MeOH/EtOAc (1.5 L) to afford methyl5-(7-carbamoyl-1H-indol-4-yl)piperidine-3-carboxylate (6.3 g, 79%):LC/MS (Table 1, Method a) R_(t)=0.96 min; MS m/z: 302 (M+H)⁺.

General Procedure AG: One Pot Borylation of a Triflate and SuzukiReaction of the In Situ Formed Boronate with an Aryl Halide

To a mixture of a vinyl triflate (preferably 1 equiv), a boronic acid orboronate ester (1 to 2 equiv, preferably 1.1 equiv), and an inorganicbase (such as KF, Na₂CO₃, K₂CO₃ or Cs₂CO₃, preferably Na₂CO₃ or Cs₂CO₃;1.1 to 16 equiv, preferably 2 equiv) in a solvent (such as THF, DME,DMF, 1,4-dioxane, 1,4-dioxane, preferably dioxane) is added a palladiumcatalyst (for example Pd(OAc)₂, Pd₂dba₃, Pd(PPh₃)₄,bis(acetato)triphenylphosphinepalladium(II), polymer-bound FibreCat™1032, SiliaCat DPP-Pd, PdCl₂(dppf) or Pd(PPh₃)₂Cl₂; preferablyPdCl₂(dppf) or Pd(PPh₃)₂Cl₂; 0.01 to 0.20 equiv, preferably 0.05 to 0.1equiv) and a ligand (for example tricyclohexylphosphine,tri-tert-butyl-phosphine; preferably none or PPh₃; 0.01 to 1.0 equiv,preferably 0.01 to 0.03 equiv) is added optionally. The mixture isheated at about 40 to 120° C. (preferably about 70 to 85° C.) for about1 to 48 h (preferably about 2 to 4 h) thermally, or at about 100 to 200°C. (preferably about 120 to 150° C.) for about 5 to 60 min (preferablyabout 20 to 45 min) in a microwave (preferably 5 min ramp time, 300Watts max power, 250 psi max pressure). The mixture is optionallyallowed to cool to rt and filtered. To the reaction mixture is added thearyl halide (1 to 2 equiv), water (about ⅓ to ¼ the volume of theoriginal organic solvent used) and optionally additional catalyst, baseand ligand is added (preferably the same ones used in the firstreaction) and heated at the same temperature for about 3 to 24 h(preferably about 8 to 10 h) and is worked up using one of the followingmethods. Method 1. For reactions containing water, the mixture may bediluted with an organic solvent (such as DCM or EtOAc). The layers areseparated, the organic solution is optionally washed with water and/orbrine, dried over anhydrous MgSO₄ or Na₂SO₄, filtered, and the solventis removed under reduced pressure to give the desired compound. Method2. The mixture is concentrated under reduced pressure. Method 3. Thecatalyst is removed by filtration and the filtrate is concentrated underreduced pressure

Illustration of General Procedure AG Preparation #AG.1: tert-Butyl6-(7-(methoxycarbonyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate

A 40 mL microwave reaction vial was charged with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.995 g,3.92 mmol), PPh₃(0.056 g, 0.214 mmol), Pd(PPh₃)₂Cl₂ (0.125 g, 0.178mmol) and K₂CO₃ (0.738 g, 5.34 mmol). To this mixture was added asolution of tert-butyl6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate(1.24 g, 3.56 mmol, Preparation #AA.1) in dioxane (13 mL). The entiremixture was degassed for about 5 min and purged with nitrogen. Themixture was heated at about 75° C. for about 2 h. To the reactionmixture was added methyl4-chloro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (0.600 g, 2.85 mmol),Pd(PPh₃)₂Cl₂ (125 mg, 0.178 mmol), K₂CO₃ (0.492 g, 3.56 mmol) and water(3.25 mL). The entire suspension was degassed with nitrogen for about 10min and heated at about 75° C. for about 8 h. The reaction mixture wascooled, filtered over a plug of Celite® and MgSO₄, concentrated andpurified via silica gel chromatography (0-40% EtOAc/heptane) to givetert-butyl6-(7-(methoxycarbonyl)-1H-pyrrolo[3,2-c]pyridin-4-yl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate(0.3 g, 23%): LC/MS (Table 1, Method as) R_(t)=2.04 min; MS m/z: 374(M+H)⁺.

General Procedure AH: Formation of an N-Tosyl Protected HeteroaromaticRing

A solution of a compound with an N-heteroaromatic ring, such as anindole or azaindole (1 equiv) in an appropriate organic solvent (such asTHF, DMF, DCE, toluene or dioxane, preferably THF) is optionally cooledto about 0° C. and a base (such as NaH, KOH or NaOH, preferable NaH; 1to 2 equiv, preferable 1.1 to 1.3 equiv) is added. The reaction mixtureis stirred for about 10 to 30 min and 4-methyl-benzenesulfonyl chloride(1 to 3 equiv, preferable 1 to 1.5 equiv) is added. The reaction mixtureis optionally allowed to warm to rt if cooled or optionally heated atabout 30 to 90° C. until complete consumption of the startingN-heteroaromatic compound. Additional base and tosylating reagent may beoptionally added as required. The reaction mixture is quenched by theaddition of water and extracted with an organic solvent (such as EtOAcor DCM). The organic layer is isolated and may optionally be washed inno particular order with water and/or aqueous solutions containing anacid (such as HCl, AcOH or NH₄Cl) and/or aqueous solutions containing abase (such as NaHCO₃, Na₂CO₃, NaOH, KOH or NH₄OH) and/or aqueoussolutions containing an inorganic salt (such as NaCl Na₂SO₃ or Na₂S₂O₃).The organic solution may then be optionally dried with a drying agent(such as anhydrous MgSO₄ or Na₂SO₄), filtered and concentrated in vacuoto give the target compound.

Illustration of General Procedure AH Preparation #AH.1:4-Bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridine-7-carbonitrile

A flask is charged with 4-bromo-1H-pyrrolo[2,3-c]pyridine-7-carbonitrile(0.985 g, 4.44 mmol, Preparation #AD.1) in THF (30 mL). NaH (60%dispersion in mineral oil, 0.213 g, 5.32 mmol) was added portion wise atabout 0° C. The mixture was allowed to stir for about 15 min, then4-methyl-benzenesulfonyl chloride (0.930 g, 4.88 mmol) was added in oneportion and the reaction was allowed to warm to room temperature andstirred or about 16 h. Additional NaH (60% dispersion in mineral oil,0.355 g, 0.89 mmol) and 4-methylbenzene-1-sulfonyl chloride (0.254 g,1.33 mmol) were added in sequence and stirred at rt for about 1 h. Thereaction mixture was diluted with water (30 mL) and extracted with EtOAc(60 mL). The organic layer was dried over MgSO₄, filtered, concentratedand purified using silica gel chromatography (0-35% EtOAc/heptane) togive 4-bromo-1-tosyl-1H-pyrrolo[2, 3-c]pyridine-7-carbonitrile (1.35 g,81%): LC/MS (Table 1, Method as) R_(t)=2.51 min; MS m/z: 376, 378(M+H)⁺.

Example #1: tert-Butyl2-(4-bromo-7-carbamoyl-1H-indol-2-yl)benzylcarbamatemethylphenyl)thiazole-2-carboxamide

Step A: tert-Butyl 2-(4-bromo-7-carbamoyl-1H-indo-2-yl)benzylcarbamate

To a solution of 4-bromo-2-iodo-1H-indole-7-carboxamide (2.5 g, 6.8mmol, Preparation #1) in THF (185 mL), MeOH (25 mL) and water (25 mL)was added tert-butyl2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (2.7 g,8.2 mmol, JW), Pd(dppf)Cl₂ (0.5 g, 0.7 mmol) and Na₂CO₃ (2.2 g, 20.6mmol). The mixture was stirred at about 80° C. overnight under nitrogen.The solvent was removed under reduced pressure to give a residue, whichwas purified by column chromatography on silica gel to provide crudetert-butyl 2-(4-bromo-7-carbamoyl-1H-indol-2-yl)benzylcarbamate (2.5 g,5.6 mmol).

Step B:tert-Butyl2-(7-carbamoyl-4-(2-methyl-3-(thiazole-2-carboxamido)phenyl)-1H-indol-2-yl)benzylcarbamate

To a solution of 2-(4-bromo-7-carbamoyl-1H-indol-2-yl)benzylcarbamate(2.5 g, 5.6 mmol) in THF (185 mL), MeOH (25 mL) and water (25 mL) wasaddedN-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazole-2-carboxamide(2.3 g, 6.8 mmol, Preparation #4), Pd(dppf)Cl₂ (0.4 g, 0.6 mmol) andNa₂CO₃ (1.8 g, 16.9 mmol). The mixture was stirred at about 80° C.overnight under nitrogen. The solvent was removed under reduced pressureto give a residue, which was purified by column chromatograph on silicagel to provide tert-butyl2-(7-carbamoyl-4-(2-methyl-3-(2-oxo-2-(thiazol-2-yl)ethyl)phenyl)-1H-indol-2-yl)benzylcarbamate(3 g, 92%): ¹H NMR (CDCl₃) δ 10.57 (s, 1H), 9.25 (s, 1H), 8.22-8.20 (d,J=7.6 Hz, 1H), 7.92-7.91 (d, J=3.2 Hz, 1H), 7.64-7.63 (d, J=3.2 Hz, 1H),7.50-7.45 (m, 3H), 7.37-7.35 (m, 3H), 7.26-7.24 (m, 2H), 7.04-7.02 (d,J=3.6 Hz, 1H), 6.32 (s, 1H), 4.43 (s, 2H), 2.25 (s, 3H), 1.38 (s, 9H).

Step C:N-(3-(2-(2-(aminomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide

A solution of tert-butyl2-(7-carbamoyl-4-(2-methyl-3-(2-oxo-2-(thiazol-2-yl)ethyl)phenyl)-1H-indol-2-yl)benzylcarbamate(3 g, 5.2 mmol) in DCM (50 mL) and TFA (10 mL) was stirred at about 25°C. for about 6 h. The solvent was removed by reduced pressure. Water wasadded and the solution was basified by addition of saturated aqueousNaHCO₃ to pH 9. The mixture was extracted with EtOAc. The organic phasewas concentrated to provideN-(3-(2-(2-(aminomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide(2.2 g, 89%): LC/MS (Table 1, Method b) R_(t)=2.53 min; MS m/z: 482(M+H)⁺. (Btk IC₅₀=B)

Example #2:4-(3-Amino-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

Step A: 4-Bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine

To a solution of 5-bromo-2-chloro-3-nitropyridine (10 g, 0.042 mol) inanhydrous THF (150 mL), a solution of vinylmagnesium bromide (17 g,0.127 mol) in THF was added dropwise at −30 to −50° C. The reactionmixture was stirred at −30 to −40° C. for 2 h. Then the reaction mixturewas poured into saturated aqueous NH₄Cl solution and the mixture wasextracted with EtOAc (50 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure and the residue was purified by column chromatographyto provide 4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine (3 g, 31%): ¹HNMR: (DMSO-d6) δ 12.45 (s, 1H), 8.04 (s, 1H), 7.79-7.78 (m, 1H),6.59-6.58 (d, J=2.0, 1H).

Step B: 3-(7-Chloro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-methylaniline

To a mixture of 4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine [Matrix] (5g, 21.6 mmol),2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.55 g,32.4 mmol, CombiBlocks) and sodium carbonate (1.6 g, 64.8 mmol) in THF(80 mL), MeOH (80 mL) and water (20 mL), Pd(dppf)Cl₂ (1.6 g, 2.16 mmol)was added and the mixture was degassed several times and heated to about70° C. overnight under N₂. The reaction mixture was filtered throughCelite© and concentrated under reduced pressure and the residue waspurified by column chromatography to provide 3-(7-chloro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-methylaniline (2.2 g, 40%): ¹H NMR (DMSO-d6) δ 12.05(s, 1H), 7.71 (s, 1H), 7.64 (d, J=2.4, 1H), 6.99-6.96 (m, 1H), 6.72-6.70(d, J=8.0, 1H), 6.48 (d, J=6.8, 1H), 6.2 (d, J=2.8, 1H), 4.95 (s, 2H),1.82 (s, 3H).

Step C: Methyl4-(3-amino-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxylate

To a solution of3-(7-chloro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-methylaniline (800 mg, 3.1mmol) in anhydrous MeOH (80 mL), Et₃N (3.1 g, 31 mmol) and Pd(dppf)Cl₂(0.45 g, 0.62 mmol) were added and the reaction mixture was heated toabout 130° C. for about 24 h under CO. The reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel column to provide methyl4-(3-amino-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxylate (0.60g, 69%): ¹H NMR (DMSO-d6): δ 11.65 (br. s., 1H), 8.09 (s, 1H) 7.65 (s,1H) 7.02 (t, J=7.72 Hz, 1H), 6.74 (d, J=7.94 Hz, 1H), 6.52 (d, J=7.50Hz, 1H) 6.26 (d, J=2.65 Hz, 1H), 5.02 (s, 2H), 4.0 (s, 3H), 1.83 (s, 3H)

Step D:4-(3-Amino-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

To a solution of methyl4-(3-amino-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxylate (600mg, 2.13 mmol) in MeOH (10 mL), ammonia (2 mL) was added and thereaction mixture was stirred overnight at rt. The mixture wasconcentrated and the residue was purified by prep-TLC (30:1 DCM/MeOH) toprovide4-(3-amino-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (320mg, 56%): ¹H NMR (DMSO-d6): δ 11.56 (s, 1H), 8.2 (s, 1H), 7.97 (s, 1H),7.64 (s, 1H), 7.55 (s, 1H), 7.0-6.97 (m, 1H), 6.71 (d, J=7.6, 1H), 6.50(d, J=4.4, 1H), 6.17 (s, 1H), 4.97 (s, 2H), 1.82 (s, 3H); (Table 1,Method d) R_(t)4=1.95 min; MS m/z: 267 (M+H)⁺. (BtkIC₅₀=C)

Example #3:N-(3-(7-carbamoyl-3-methyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide

Step A: Methyl 4-bromo-3-formyl-1H-indole-7-carboxylate

POCl₃ (2.4 mL, 26 mmol) was added into DMF (60 mL) solution dropwise at0° C. and stirred for about 30 min. Then a solution of methyl4-bromo-1H-indole-7-carboxylate (5 g, 13 mmol, Preparation #1, step B)in DMF (60 mL) was added dropwise into the above reaction mixture atabout 0° C. and stirred for about 20 min. The resulting reaction mixturewas heated to about 90° C. for about 3 h. After cooling to rt, themixture was poured into ice water and basified by addition of aqueousNaOH solution to pH=8 to 9. The aqueous mixture was extracted withEtOAc. The combined organic phase was washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure to get aresidue, which was purified by column chromatography on silica gel toprovide methyl 4-bromo-3-formyl-1H-indole-7-carboxylate (3.5 g, 95%): ¹HNMR (DMSO-d6): δ 12.33 (br, 1H), 10.69 (s, 1H), 8.20 (d, J=2.0 Hz, 1H),7.76-7.74 (d, J=8.0 Hz, 1H), 7.61-7.59 (d, J=8.4 Hz, 1H), 3.94 (s, 3H).

Step B: Methyl4-bromo-3-(((4-methoxybenzyl)amino)methyl)-1H-indole-7-carboxylate

To a solution of methyl 4-bromo-3-formyl-1H-indole-7-carboxylate (3.5 g,12.4 mmol) in anhydrous DCE (50 mL) was added(4-methoxyphenyl)methanamine (2.6 g, 18.6 mmol) and a catalyst amount ofAcOH. The reaction mixture was stirred at rt for about 1 h. ThenNaBH(OAc)₃ (13.2 g, 62 mmol) was added in portions and stirred at rtovernight. When the reaction was completed, water was added to quenchthe reaction. The aqueous phase was extracted with DCM. The combinedorganic phase was concentrated under reduced pressure to get a residue,which was purified by column chromatography on silica gel to providemethyl4-bromo-3-(((4-methoxybenzyl)amino)methyl)-1H-indole-7-carboxylate (4 g,80%): ¹H NMR (DMSO-d6): δ 11.25 (br, 1H), 7.61-7.59 (d, J=8.4 Hz, 1H),7.41 (s, 1H), 7.30-7.23 (m, 3H), 6.85-6.83 (d, J=8.4 Hz, 2H), 4.02 (s,2H), 3.90 (s, 3H), 3.70-3.69 (m, 5H), 1.88 (s, 1H).

Step C:4-Bromo-3-(((4-methoxybenzyl)amino)methyl)-1H-indole-7-carboxylicacid

To a solution of methyl4-bromo-3-(((4-methoxybenzyl)amino)methyl)-1H-indole-7-carboxylate (5.4g, 13.4 mmol) in THF (250 mL), MeOH (50 mL) and water (50 mL) was addedLiOH (1.6 g, 67.0 mmol) and heated to reflux for about 6 h. Aftercooling to rt, the organic solvent was removed under reduced pressure.The aqueous phase was acidified with 1 N HCl to pH=5 to 6. Then thesuspension was filtered and the filter cake was washed with water anddried to afford4-bromo-3-(((4-methoxybenzyl)amino)methyl)-1H-indole-7-carboxylic acid(4 g, 77%): ¹H NMR (DMSO-d6) δ 11.40 (br, 1H), 7.58-7.56 (d, J=8.0 Hz,1H), 7.53 (s, 1H), 7.40-7.38 (d, J=8.4 Hz, 2H), 7.27-7.25 (d, J 8.0 Hz,1H), 6.94-6.92 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 3.98 (s, 2H), 3.74 (s,3H).

Step D:4-Bromo-3-(((4-methoxybenzyl)amino)methyl)-1H-indole-7-carboxamide

A mixture of4-bromo-3-(((4-methoxybenzyl)amino)methyl)-1H-indole-7-carboxylic acid(9.3 g, 23.9 mmol), EDCI (5.5 g, 28.7 mmol) and HOBt (4.4 g, 28.7 mmol)in THF (350 mL) and DCM (420 mL) was stirred at rt for about 1 h. Thenthe reaction mixture was bubbled with ammonia gas for about 15 min atabout −60° C., then warmed to rt and stirred overnight. The solvent wasremoved under reduced pressure and MeOH was added. The suspension wasfiltered and the filtrated was concentrated under reduced pressure toget a residue, which was purified by Prep-HPLC (Table 1, Method s) toprovide4-bromo-3-(((4-methoxybenzyl)amino)methyl)-1H-indole-7-carboxamide (2.1g, 23%): LC/MS (Table 1, Method d) R_(t)4=2.31 min; MS m/z: 388 (M+H)⁺

Step E:N-(3-(7-carbamoyl-3-(((4-methoxybenzyl)amino)methyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide

To a solution of4-bromo-3-(((4-methoxybenzyl)amino)methyl)-1H-indole-7-carboxamide (100mg, 0.26 mmol),N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazole-2-carboxamide(116 mg, 0.39 mmol, Preparation #4) and CsF (39 mg, 0.26 mmol) in1,4-dioxane (2 mL) and water (0.4 mL) was added Pd(PPh₃)₄ (29.8 mg, 0.03mmol). Then the reaction mixture was heated to about 100° C. undernitrogen for about 12 h. After cooling to rt, water was added andextracted with EtOAc. The combined organic phase was washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure toget a crude product, which was purified by Prep-HPLC (Table 1, Method r)to provideN-(3-(7-carbamoyl-3-(((4-methoxybenzyl)amino)methyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide(10 mg, 8%): ¹H NMR (DMSO-d6): δ 11.05 (br, 1H), 10.23 (br, 1H),8.14-8.10 (m, 3H), 7.72-7.65 (m, 2H), 7.27 (br, 1H), 7.26-7.24 (m, 2H),7.11-7.09 (m, 1H), 7.02-7.00 (d, J=8.8 Hz, 2H), 6.77-6.71 (m, 3H), 3.63(s, 3H), 3.24-3.21 (m, 4H), 1.88 (s, 3H), 1.83 (s, 1H)

Step F:N-(3-(7-carbamoyl-3-methyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide

To a solution ofN-(3-(7-carbamoyl-3-(((4-methoxybenzyl)amino)methyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide(10 mg, 0.02 mmol) in anhydrous MeOH (5 mL) was added dry Pd/C (5 mg)and stirred at rt under hydrogen (50 Psi) overnight. Then the reactionmixture was filtered and the filtrated was concentrated under reducedpressure to get a residue, which was purified by Prep-HPLC (Table 1,Method q) to provideN-(3-(7-carbamoyl-3-methyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide(1.1 mg, 15%): LC/MS (Table 1, Method j) R_(t)=3.05 min; MS m/z: 391(M+H)⁺. (Btk IC₅₀=B)

Example #4:N-(3-(7-carbamoyl-3-methyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide

Step A: 5-Bromo-6-nitroindoline

To a solution of 5-bromoindoline (12.33 g, 83 mmol) in H₂SO₄ (60 mL) wasadded KNO₃ (7.55 mL, 74.7 mmol) at about 0° C. The solution was stirredat 0-10° C. for about 1 h, and then the mixture was stirred overnight atrt. The mixture was poured into ice water, basified with NaCO₃ to aboutpH 8. The mixture was extracted with EtOAc (300 mL×3), the organic phasewas dried with NaSO₄, concentrated under reduced pressure and theresidue was purified by column chromatography on silica gel (Petether:EtOAc=20:1) to provide 5-bromo-6-nitroindoline (12.3 g, 81%): ¹HNMR (CDCl₃) δ 7.25 (s, 1H), 6.91 (s, 1H), 3.98 (s, 1H), 3.66-3.56 (m,2H), 3.08-2.96 (m, 2H).

Step B: tert-Butyl 5-bromo-6-nitroindoline-1-carboxylate

To a solution of 5-bromo-6-nitroindoline (7.5 g, 30.9 mmol) in DCM (750mL) was added (Boc)₂O (13.47 g, 61.7 mmol) at 0° C. Then Et₃N (9.37 g,93 mmol) and DMAP (0.337 g, 3.09 mmol) were added to the mixture. Themixture was stirred overnight at rt. The reaction mixture was pouredinto water, extracted with DCM (300 mL×3) and the organic phase wasdried with NaSO₄, concentrated under reduced pressure and the residuewas purified by silica gel column (Pet ether:EtOAc=30:1) to providetert-butyl 5-bromo-6-nitroindoline-1-carboxylate (6.7 g, 63%): ¹H NMR(CDCl₃) δ 8.29 (s, 1H), 7.42 (s, 1H), 4.06 (s, 2H), 3.18-3.13 (m, 2H)1.57 (s, 9H).

Step C: tert-Butyl5-bromo-2,3-dihydropyrrolo[2,3-e]indole-1(6H)-carboxylate

To a mixture of tert-butyl 5-bromo-6-nitroindoline-1-carboxylate (4 g,11.66 mmol) in THF (60 mL) was added vinylmagnesium bromide (6.43 g,49.0 mmol) at −40 to 50° C., then the resulting mixture was stirred at−20 to −30° C. for about 2 h, and then overnight at rt. The mixture waspoured into saturated NH₄Cl solution and extracted with EtOAc (100mL×3). The organic phase was dried with NaSO₄, concentrated underreduced pressure and the residue was purified by gel chromatographysilica (Pet ether:EtOAc=50:1) to provide tert-butyl5-bromo-2,3-dihydropyrrolo[2,3-e]indole-1(6H)-carboxylate (0.7 g, 18%):¹H NMR (CDCl₃) δ 8.17 (s, 1H), 7.13-7.10 (m, 2H), 7.07 (m, 1H),4.05-4.00 (t, J=8.4 Hz, 2H), 3.07-3.03 (t, J=8.4 Hz, 2H), 1.5 (s, 9H).

Step D: 1,2,3,6-Tetrahydropyrrolo[2,3-e]indole-5-carbonitrile

To the solution of tert-butyl5-bromo-2,3-dihydropyrrolo[2,3-e]indole-1(6H)-carboxylate (60 mg, 0.178mmol) in DMF (2 mL) was added Zn (CN)₂ (12.53 mg, 0.107 mmol) andPd(PPh₃)₄ (20.56 mg, 0.018 mmol). The solution was heated at about 145°C. for about 50 min by microwave under N₂. The mixture was concentratedunder reduced pressure and the residue was purified by prep-HPLC (Table1, Method aj) to provide1,2,3,6-tetrahydropyrrolo[2,3-e]indole-5-carbonitrile (20 mg, 61%): HNMR (MeOD): δ 7.34 (s, 1H), 7.30 (d, J=3.2, 1H), 6.51 (d, J=3.2, 1H),3.82-3.78 (t, J=8 Hz, 2H), 3.23-3.18 (t, J=8.4 Hz, 2H).

Step E: 1,2,3,6-Tetrahydropyrrolo[2,3-e]indole-5-carboxamide

To a solution of 1,2,3,6-tetrahydropyrrolo[2,3-e]indole-5-carbonitrile(160 mg, 0.873 mmol) in DMSO (4 mL), K₂CO₃ (300 mg, 2.171 mmol) wasadded, then H₂O₂ (4 mL, 39.2 mmol) was added dropwise at rt. And thereaction mixture was stirred overnight at rt. The mixture was pouredinto water, extracted with EtOAc (20 mL×3) and the organic phase waswashed by saturated aqueous Na₂S₂O₃, dried and concentrated and theresidue was purified by prep-HPLC (Table 1, Method ak) to provide1,2,3,6-tetrahydropyrrolo[2,3-e]indole-5-carboxamide (70 mg, 40%): LC/MS(Table 1, Method d) R_(t)=1.43 min; MS m/z: 202 (M+H)⁺.

Step F: 1-Acryloyl-1,2,3,6-tetrahydropyrrolo[2,3-e]indole-5-carboxamide

To a solution of 1,2,3,6-tetrahydropyrrolo[2,3-e]indole-5-carboxamide(15 mg, 0.075 mmol) in DCM (10 mL), Et₃N (1 mL, 7.17 mmol) was added,and then a solution of acryloyl chloride (10 mg, 0.11 mmol) in DCM (0.5mL) was added dropwise at 0° C. The reaction mixture was stirredovernight ar rt. The reaction solution was concentrated under reducedpressure and the residue was purified by prep-HPLC (Table 1, Method t)to provide1-acryloyl-1,2,3,6-tetrahydropyrrolo[2,3-e]indole-5-carboxamide (12 mg,63%): ¹H NMR: (DMSO-d6) δ 11.13 (s, 1H), 7.93 (s, 1H), 7.61 (s, 1H),7.21 (s, 2H), 6.8-6.73 (m, 2H), 6.34-6.30 (m, 1H), 5.84-5.82 (d, J=10.4,1H), 4.25-4.21 (t, J=8.0, 2H), 3.21-3.13 (m, 2H); LC/MS (Table 1, Methodd) R_(t)=2.39 min; MS m/z: 256 (M+H)⁺. (Btk IC₅₀=B)

Example #5: 4-Acrylamido-1H-indole-7-carboxamide

Step A: 4-Amino-1-tosyl-1H-indole-7-carbonitrile

To a solution of 4-fluoro-1-tosyl-1H-indole-7-carbonitrile (500 mg, 1.59mmol, Preparation #27, step A) in 1,4-dioxane (5 mL), ammonia (2.5 mL,116 mmol) was added. The mixture was stirred at about 120° C. overnight.The reaction mixture was concentrated under reduced pressure and theresidue was purified by silica gel column to provide4-amino-1-tosyl-1H-indole-7-carbonitrile (100 mg, 20%): ¹H NMR(DMSO-d6): δ 7.86-7.84 (m, 2H), 7.77-7.76 (d, J=4, 1H), 7.46-7.44 (d,J=8, 2H), 7.37-7.35 (d, J=8, 1H), 7.12 (s, 1H), 6.70 (s, 2H), 6.46-6.44(d, J=8, 1H), 2.37 (s, 3H).

Step B: 4-Amino-1H-indole-7-carbonitrile

To a solution of 4-amino-1-tosyl-1H-indole-7-carbonitrile (90 mg, 0.289mmol) in THF (2 mL), MeOH (1 mL) and water (1 mL) was added LiOH (69 mg,2.89 mmol). The mixture was stirred at about 40° C. overnight. Thereaction mixture was concentrated under reduced pressure, water wasadded, and extracted with EtOAc (20 mL×3) The combined organics weredried over Na₂SO₄, filtered, and concentrated under reduced pressure toprovide 4-amino-1H-indole-7-carbonitrile (40 mg, 88%): ¹H NMR (DMSO-d6):δ 11.43 (s, 1H), 7.21-7.19 (d, J=8, 1H), 7.13-7.12 (m, 1H), 6.67-6.62(m, 1H), 6.20-6.18 (d, J=8, 1H).

Step C: 4-Amino-1H-indole-7-carboxamide

To a solution of 4-amino-1H-indole-7-carbonitrile (40 mg, 0.254 mmol) inDMSO (2 mL), K₂CO₃ (52.8 mg, 0.382 mmol) and 30% H₂O₂ (2 mL) were addedat rt. The reaction mixture was stirred at rt for 5 h. Water was addedto the reaction mixture and the mixture was extracted with EtOAc (20mL×3) and the organic phase was dried over Na₂SO₄, concentrated underreduced pressure and the residue was purified by prep-TLC(DCM:MeOH=15:1) to provide 4-amino-1H-indole-7-carboxamide (30 mg, 67%):¹H NMR (DMSO-d6) δ 10.79 (s, 1H), 7.43-7.41 (d, J=8, 1H), 7.04 (s, 1H),6.52 (s, 1H), 6.10-6.08 (d, J=8, 1H), 5.83 (s, 2H).

Step D: 4-Acrylamido-1H-indole-7-carboxamide

To a solution of 4-amino-1H-indole-7-carboxamide (30 mg, 0.171 mmol) inDCM (3 mL), DIEA (0.060 mL, 0.342 mmol) and acryloyl chloride (18.60 mg,0.205 mmol) were added and the reaction mixture was stirred overnight atrt. Then the reaction mixture was concentrated under reduced pressureand the residue was purified by prep-HPLC (Table 1, Method u) to provide4-acrylamido-1H-indole-7-carboxamide (17 mg, 43%): LC/MS (Table 1,Method d) R_(t)=2.10 min; MS m/z: 230 (M+H)⁺. (Btk IC₅₀=C)

Example #6: 4-Acrylamido-1H-indole-7-carboxamide

Step A:4-(3-Acrylamido-5-aminophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide

To a round bottom flask was added4-(3-acrylamido-5-nitrophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide(0.175 g, 0.343 mmol, prepared using A from4-bromo-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide(Preparation #18) and 3-amino-5-nitrophenylboronic acid hydrochloride[CombiBlocks], E and acryloyl chloride) in NMP (2 mL) and HCl, 37%(0.222 mL) to give a red suspension. The reaction was heated to about85° C. and tin (II) chloride (0.600 g, 0.316 mmol) was added. Thereaction was stirred at about 85° C. for about 1.5 h. Additional tin(II) chloride (2.39 g, 1.26 mmol) was added and the reaction was furtherstirred at about 85° C. for about 2 h. The reaction was cooled to rt andDCM (30 mL), MeOH (10 mL), and 1N NaOH (15 mL) were added. The mixturewas stirred vigorously for about 2 h, filtered, and the filtrateextracted with DCM (3×). The organic layers were combined and thesolvent removed under vacuum. Water and EtOAc was added to the residueand extracted with EtOAc (4×). The organic layers were combined andwashed with water and brine. The organic layers were combined andsolvent removed under vacuum. The crude product was added to a silicagel column and was eluted with 0-10% MeOH in DCM. The material wasfurther purified by prep-HPLC (Table 1, Method ag) to provide4-(3-acrylamido-5-aminophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide(20 mg, 12%): LC/MS (Table 1, Method g) R_(t)=1.12 min.; MS m/z: 480(M+H)⁺.

Step B:4-(3-Acrylamido-5-(thiazol-2-ylmethylamino)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide

To a stirring solution of4-(3-acrylamido-5-aminophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide(20 mg, 0.042 mmol) and thiazole-2-carbaldehyde (4.03 μL, 0.046 mmol) inMeOH (1 mL) was added MP-Cyanoborohydride (88 mg, 0.167 mmol) and aceticacid (9.55 μL, 0.167 mmol). The slurry was stirred at about 40° C. forabout 40 h. The suspension was filtered and the resin washed with DCMand MeOH. The filtrate was passed through a plug of Si-carbonate. Thefiltrate was concentrated under reduced pressure and the residue waspurified by Prep-TLC (10% MeOH/DCM) follow by a second purification byPrep-TLC (5% MeOH/DCM) to provide4-(3-acrylamido-5-(thiazol-2-ylmethylamino)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide(7.2 mg, 25%): LC/MS (Table 1, Method g) R_(t)=1.56 min.; MS m/z: 577(M+H)⁺. (Btk IC₅₀=A)

Example #7:(E)-4-(3-(2-Cyano-3-hydroxybut-2-enamido)phenyl)-1H-indole-7-carboxamide

A mixture ofN-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-5-methylisoxazole-4-carboxamide(0.060 g, 0.166 mmol, Example #E.2.1) and NaOH (0.008 g, 0.200 mmol) inMeOH (1.9 mL) was heated in a vial at about 60° C. After about 2 h, thereaction was cooled to rt and 1N aqueous HCl was added to acidify. Theresulting precipitate was collected via vacuum filtration to provide(E)-4-(3-(2-cyano-3-hydroxybut-2-enamido)phenyl)-1H-indole-7-carboxamide(0.047 g, 78%) as a solid after drying under vacuum at about 55° C.:LC/MS (Table 1, Method c) R_(t)=2.79 min.; MS m/z: 361 (M+H)⁺. (BtkIC₅₀=C)

Example #8: 4-(cis-3-Acrylamidocyclohexyl)-1H-indole-7-carboxamide andExample #9. 4-(trans-3-Acrylamidocyclohexyl)-1H-indole-7-carboxamide

Step A: tert-Butyl(3-(7-carbamoyl-1H-indol-4-yl)cyclohex-2-en-1-yl)carbamate andtert-Butyl (3-(7-carbamoyl-1H-indol-4-yl)cyclohex-3-en-1-yl)carbamate

To a solution of 4-bromo-1H-indole-7-carboxamide (296 mg, 1.237 mmol,Preparation #2), a mixture of[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-cyclohex-3-enyl]-carbamicacid tert-butyl ester and[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclohex-2-enyl]-carbamicacid tert-butyl ester (400 mg, 1.237 mmol, U.S. 2009/0197864), Na₂CO₃(328 mg, 3.09 mmol), PdCl₂(dppf)-DCM Adduct (101 mg, 0.124 mmol) inTHF:MeOH:H₂O (Ratio: 4:2:2, 20 mL) under N₂ atmosphere, the mixture washeated at about 100° C. overnight. The reaction mixture was filteredthrough a pad of Celite©. The resulting mixture was diluted with EtOAc(30 mL), washed with H₂O (20 mL×2), dried with Na₂SO₄, concentratedunder reduced pressure and the residue was purified by prep-HPLC (Table1, Method x) to provide a mixture of tert-butyl(3-(7-carbamoyl-1H-indol-4-yl)cyclohex-2-en-1-yl)carbamate andtert-butyl (3-(7-carbamoyl-1H-indol-4-yl)cyclohex-3-en-1-yl)carbamate(300 mg, 68%): LC/MS (Table 1, Method 1) R_(t)=1.67 min; MS m/z: 356(M+H)⁺.

Step B: tert-Butyl (3-(7-carbamoyl-1H-indo-4-yl)cyclohexyl)carbamate

To a solution of tert-butyl(3-(7-carbamoyl-1H-indol-4-yl)cyclohex-2-en-1-yl)carbamate andtert-butyl (3-(7-carbamoyl-1H-indol-4-yl)cyclohex-3-en-1-yl)carbamate(300 mg, 0.844 mmol) in THF (20 mL), Pd/C (44.9 mg, 0.422 mmol) wasadded and the reaction mixture was stirred at rt for about 3 h under H₂atmosphere. The mixture was filtered and concentrated under reducedpressure to give crude product tert-butyl(3-(7-carbamoyl-1H-indol-4-yl)cyclohexyl)carbamate (290 mg, 96%), whichwas used to next step directly. LC/MS (Table 1, Method 1) R_(t)=1.53min; MS m/z: 358 (M+H)⁺.

Step C: 4-(3-Aminocyclohexyl)-1H-indole-7-carboxamide

To a solution of tert-butyl(3-(7-carbamoyl-1H-indol-4-yl)cyclohexyl)carbamate (220 mg, 0.615 mmol)in MeOH (10 mL), MeOH/HCl (10 mL) was added at about 0° C., then thereaction mixture was stirred at rt for about 3 h. The reaction mixturewas concentrated under reduced pressure to give crude product4-(3-aminocyclohexyl)-1H-indole-7-carboxamide (100 mg, 63%), which wasused to next step directly. LC/MS (Table 1, Method 1) R_(t)=0.54 min; MSm/z: 258 (M+H)⁺.

Step D: 4-(cis-3-Acrylamidocyclohexyl)-1H-indole-7-carboxamide and4-(trans-3-Acrylamidocyclohexyl)-1H-indole-7-carboxamide

To a solution of 4-(3-aminocyclohexyl)-1H-indole-7-carboxamide (120 mg,0.466 mmol) in DCM (3 mL), DIEA (120 mg, 0.933 mmol) was added, acryloylchloride (42.2 mg, 0.466 mmol) was added at about 0° C. dropwise and themixture was stirred at about 0° C. for about 10 min, then concentratedunder reduced pressure and the residue was purified by prep-HPLC (Table1, Method y) to provide4-(cis-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide (27 mg, 19%) 1HNMR: (MeOD) δ 7.59 (d, J=8, 1H), 7.33 (d, J=3.2, 1H), 6.95 (d, J=8, 1H),6.64 (d, J=4, 1H), 6.26-6.17 (m, 2H), 5.67-5.58 (m, 1H), 4.01-3.96 (m,1H), 3.22-3.13 (m, 1H), 2.19-1.97 (m, 4H), 1.65-1.59 (m, 3H), 1.37-1.34(m, 1H); LC/MS (Table 1, Method d) R_(t)=2.56 min; MS m/z: 312 (M+H)⁺.(Btk IC₅₀=A) and4-(trans-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide (33 mg, 23%):¹H NMR (MeOD) δ 7.58 (d, J=8, 1H), 7.31 (d, J=3.2, 1H), 6.98 (d, J=8,1H), 6.59 (d, J=2.8, 1H), 6.52-6.46 (m, 1H), 6.28-6.24 (m, 1H),5.69-5.64 (m, 1H), 4.35 (s, 1H), 3.42-3.36 (m, 1H), 2.13-1.72 (m, 8H);LC/MS (Table 1, Method d) R_(t)=2.56 min; MS m/z: 312 (M+H)⁺. (BtkIC₅₀=B)

Examples #10 and #11:4-(cis-3-Acrylamidocyclopentyl)-1H-indole-7-carboxamide and4-(trans-3-Acrylamidocyclopentyl)-1H-indole-7-carboxamide

Step A: 3-((tert-Butoxycarbonyl)amino)cyclopent-1-en-1-yltrifluoromethanesulfonate and4-((tert-butoxycarbonyl)amino)cyclopent-1-en-1-yltrifluoromethanesulfonate

To a freshly prepared LDA solution (2M in THF, 9.38 mL) was addedtert-butyl (3-oxocyclopentyl)carbamate (2.00 g, 10.0 mmol) in THF (4 mL)at about −78° C. dropwise. The mixture was warmed to rt for about 30 minand then cooled to about −78° C. again. A solution of1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(5.38 g, 15.1 mmol) in THF (10 mL) was added dropwise to the reactionmixture at about −78° C. The resulting mixture was warmed to rt andstirred for another 3 h. Treated with EtOAc (30 mL), the mixture waswashed with H₂O (20 mL×3) and brine (10 mL), dried with Na₂SO₄,concentrated under reduced pressure and the residue was purified bychromatography on silica gel to provide a mixture of3-((tert-butoxycarbonyl)amino)cyclopent-1-en-1-yltrifluoromethanesulfonate and4-((tert-butoxycarbonyl)amino)cyclopent-1-en-1-yltrifluoromethanesulfonate (0.82 g, 25%), which was used in next stepwithout further purification.

Step B: tert-Butyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-yl)carbamateand tert-butyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-3-en-1-yl)carbamate

A mixture of 3-((tert-butoxycarbonyl)amino)cyclopent-1-en-1-yltrifluoromethanesulfonate and4-((tert-butoxycarbonyl)amino)cyclopent-1-en-1-yltrifluoromethanesulfonate (720 mg, 2.173 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (662 mg,2.61 mmol), PdCl₂(dppf)-DCM adduct (177 mg, 0.217 mmol) and KOAc (427mg, 4.35 mmol) in 1,4-dioxane (20 mL) under N₂ atmosphere was heated atabout 100° C. overnight. The resulting mixture was diluted with DCM (30mL), washed with H₂O (20 mL×2), concentrated under reduced pressure andthe residue was purified by silica gel to give crude mixture oftert-butyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-yl)carbamateand tert-butyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-3-en-1-yl)carbamate(0.42 g, 63%), which was used directly in the next step without furtherpurification.

Step C: tert-Butyl(3-(7-carbamoyl-1H-indol-4-yl)cyclopent-2-en-1-yl)carbamate andtert-butyl (3-(7-carbamoyl-1H-indol-4-yl)cyclopent-3-en-1-yl)carbamate

To a solution of 4-bromo-1H-indole-7-carboxamide (325 mg, 1.36 mmol,Preparation #2), tert-butyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-yl)carbamateand tert-butyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-3-en-1-yl)carbamate(420 mg, 1.36 mmol), Na₂CO₃ (360 mg, 3.4 mmol), PdCl₂(dppf)-DCM Adduct(111 mg, 0.136 mmol) in THF:MeOH:H₂O (Ratio: 4:2:2, 15 mL) under N₂atmosphere, the mixture was stirred at about 100° C. overnight. Thereaction mixture was filtered to remove Pd complex. The resultingmixture was diluted with EtOAc (30 mL), washed with H₂O (20 mL×2), driedwith Na₂SO₄, concentrated and purified by prep-HPLC (Table 1, Method y)to provide a mixture of tert-butyl(3-(7-carbamoyl-1H-indol-4-yl)cyclopent-2-en-1-yl)carbamate andtert-butyl (3-(7-carbamoyl-1H-indol-4-yl)cyclopent-3-en-1-yl)carbamate(0.32 g, 69%): LC/MS (Table 1, Method 1) R_(t)=1.65 min; MS m/z: 342(M+H)⁺.

Step D: tert-Butyl (3-(7-carbamoyl-1H-indol-4-yl)cyclopentyl)carbamate

To a solution of tert-butyl(3-(7-carbamoyl-1H-indol-4-yl)cyclopent-2-en-1-yl)carbamate andtert-butyl (3-(7-carbamoyl-1H-indol-4-yl)cyclopent-3-en-1-yl)carbamate(300 mg, 0.844 mmol) in THF (20 mL), Pd/C (44.9 mg, 0.422 mmol) wasadded and the the mixture was stirred for about 3 h at rt under H₂. Themixture was filtered and concentrated under reduced pressure to providecrude tert-butyl (3-(7-carbamoyl-1H-indol-4-yl)cyclopentyl)carbamate(0.29 g, 96%), which was used to next step directly without furtherpurification. LC/MS (Table 1, Method 1) R_(t)=1.50 min; MS m/z: 344(M+H)⁺.

Step E: 4-(cis-3-Aminocyclopentyl)-1H-indole-7-carboxamide and4-(trans-3-aminocyclopentyl)-1H-indole-7-carboxamide

To a solution of tert-butyl(3-(7-carbamoyl-1H-indol-4-yl)cyclopentyl)carbamate (250 mg, 0.728 mmol)in MeOH (10 mL), MeOH/HCl (10 mL) was added at about 0° C. and themixture was stirred for about 3 h at rt. The mixture was concentratedunder reduced pressure and the residue was purified by prep-HPLC (Table1, Method t) to provide4-(trans-3-aminocyclopentyl)-1H-indole-7-carboxamide (10 mg, 6%) and4-(cis-3-aminocyclopentyl)-1H-indole-7-carboxamide (50 mg, 28%). To asolution of 4-(cis-3-aminocyclopentyl)-1H-indole-7-carboxamide (50 mg,0.206 mmol) in DCM (3 mL), DIEA (53 mg, 0.411 mmol) was added, thenacryloyl chloride (18.60 mg, 0.206 mmol) was added dropwise at about 0°C., the mixture was stirred at about 0° C. for about 10 min, thenconcentrated under reduced pressure and the residue was purified byprep-HPLC (Table 1, Method z) to give4-(cis-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide (20 mg, 33%): ¹HNMR (MeOD) δ 7.59 (d, J=7.2, 1H), 7.33 (s, 1H), 7.02 (d, J=8, 1H), 6.64(s, 1H), 6.30-6.20 (m, 2H), 5.64 (d, J=8.8, 1H), 4.51-4.40 (m, 1H),3.60-3.58 (m, 1H), 2.56-2.51 (m, 1H), 2.26-2.21 (m, 2H), 2.07-2.02 (m,1H), 1.86-1.78 (m, 2H): LC/MS (Table 1, Method d) R_(t)=2.48 min; MSm/z: 298 (M+H)⁺. (Btk IC₅₀=A) To a solution of4-(trans-3-aminocyclopentyl)-1H-indole-7-carboxamide (10 mg, 0.041 mmol)in DCM (1 mL), DIEA (11 mg, 0.082 mmol) was added, then acryloylchloride (3.72 mg, 0.041 mmol) was dropwise added, the mixture wasstirred at about 0° C. for about 10 min, concentrated and purified byprep-HPLC (Table 1, Method z) to give4-(trans-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide (1.1 mg, 9%):¹H NMR (MeOD) δ 7.60 (d, J=7.6, 1H), 7.33 (d, J=2.8, 1H), 7.00 (d,J=7.6, 1H), 6.62 (d, J=3.2, 1H), 6.33-6.20 (m, 2H), 5.67-5.64 (m, 1H),4.50-4.49 (m, 1H), 3.81-3.72 (m, 1H), 2.34-2.28 (m, 3H), 2.26-2.23 (m,1H), 2.07-1.89 (m, 1H), 1.88-1.74 (m, 1H); LC/MS (Table 1, Method d)R_(t)=2.47 min; MS m/z: 298 (M+H)⁺. (BtkIC₅₀=A)

Example #12*:(R)-2-(1-(Methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-oxo-1,3′-bipiperidin-1′-yl)-1H-indole-7-carboxamide

Step A:(R)-2-(1-(Methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-oxo-1,3′-bipiperidin-1′-yl)-1-tosyl-1H-indole-7-carbonitrile

To a solution of (R)-tert-butyl 2-oxo-1,3‘-bipiperidine-1’-carboxylate(100 mg, 0.354 mmol, WO 2011/029046) in DCM (4 mL) was added TFA (1.000mL). The reaction was stirred for about 4 h at rt. The solvent wasstripped off and a mixture of4-fluoro-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-tosyl-1H-indole-7-carbonitrile(168 mg, 0.354 mmol, Preparation #27) and TEA (0.197 mL, 1.417 mmol) inDMSO (2 mL) was added. The vial was sealed and the reaction was heatedin a microwave at about 120° C. for about 30 min. Water (20 mL) wasadded and extracted into DCM then washed with brine and passed through aphase separatore to remove residual water. Evaporated andchromatographed on silica to eluting with a gradent of 0-100%EtOAc/hexane to provide crude(R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-oxo-1,3′-bipiperidin-1′-yl)-1-tosyl-1H-indole-7-carbonitrile(0.041 g, 18.21%).

Step B:(R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-oxo-1,3′-bipiperidin-1′-yl)-1H-indole-7-carboxamide

A mixture of Cs₂CO₃ (20.50 mg, 0.063 mmol) and(R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-oxo-1,3′-bipiperidin-1′-yl)-1-tosyl-1H-indole-7-carbonitrile(40 mg, 0.063 mmol) in THF (2 mL) and MeOH (1.000 mL) were stirred at rtovernight. The solution was diluted with water (15 mL) and stirred forabout 20 min. DCM was added to dissolve the suspension and the mixturewas filtered through a Biotage phase separator. The organics werecollected and concentrated. The intermediate was dissolved in t-butanol(1 mL) and DMSO (0.500 mL) and NaOH (0.377 mL, 0.755 mmol) and hydrogenperoxide (0.175 mL, 1.699 mmol) were added. The mixture was stirred forabout 20 min at rt and saturated NH₄Cl (1 mL) was added. The mixture wasdiluted with water (15 mL) and stirred for about 15 min. The solids werecollected by filtration washing several times with water and dried undervacuum and purified by prep-HPLC (Table 1, Method aq). The samples werereturned and dissolved in DCM. The organics were combined and washedwith saturated sodium bicarbonate, filtered through a Biotage phaseseparator, and concentrated to provide(R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-oxo-1,3′-bipiperidin-′-yl)-1H-indole-7-carboxamide(3 mg, 9.54%): LC/MS (Table 1, Method f) R_(t)=1.37 min; MS m/z: 500(M+H)⁺. (Btk IC₅₀=B)

Example #13*:(R)-2-(1-(Methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide

Step A: (R)-2-Methyl-N-(piperidin-3-yl)benzamide

A mixture of (R)-tert-butyl3-(2-methylbenzamido)piperidine-1-carboxylate (19.0 g, 59.7 mmol,prepared using D from (R)-tert-butyl 3-aminopiperidine-1-carboxylate and2-methylbenzoic acid) in HCl (2 N in MeOH, 300 mL, 600 mmol) was stirredat rt for about 4 h, then concentrated under reduced pressure to providecrude (R)-2-methyl-N-(piperidin-3-yl)benzamide (20.0 g), which was useddirectly for the next step without further purification.

Step B: (R)—N-(1-Benzylpiperidin-3-yl)-2-methylbenzamide

To a solution of (R)-2-methyl-N-(piperidin-3-yl)benzamide (20.0 g,crude) and TEA (30.1 g, 298.5 mmol) in DCM (260 mL) was added dropwiseBnBr (11.2 g, 65.7 mmol) at rt over about 30 min. Then the mixture wasstirred at rt overnight. After completion, DCM (1 L) was added, and themixture was washed with H₂O (3×100 mL). The organic phase was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to provide(R)—N-(1-benzylpiperidin-3-yl)-2-methylbenzamide (12.0 g, 65% over twosteps): LC/MS (Table 1, Method 1) R_(t)=0.91 min; MS m/z: 309 (M+H)⁺.

Step C: (R)-2-(1-Benzylpiperidin-3-yl)isoquinolin-1(2H)-one

To the solution of (R)—N-(1-benzylpiperidin-3-yl)-2-methylbenzamide(12.0 g, 38.9 mmol) in THF was added dropwise n-BuLi (2.5 M, 32.7 mL)between −22 and −14° C., over about 30 min. The resulting deep redsolution was stirred at about −22° C. for about 30 min and DMF was addedbelow about −14° C. (internal). After the addition was completed, thesolution was stirred at about −22° C. for about 30 min. Then HCl (6 Naqueous, 25 mL, 150 mmol) was slowly added, keeping the temperaturebelow 5° C. The mixture was basified by addition of saturated NaOH atabout 0° C. to pH 14 and extracted with DCM (3×500 mL). The organicphase was dried over Na₂SO₄ and concentrated under reduced pressure toprovide (R)-2-(1-benzylpiperidin-3-yl)isoquinolin-1(2H)-one (12.0 g,97%) as a solid: LC/MS (Table 1, Method 1) R_(t)=1.35 min; MS m/z: 319(M+H)⁺.

Step D: (R)-2-(Piperidin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one

A mixture of (R)-2-(1-benzylpiperidin-3-yl)isoquinolin-1(2H)-one (12 g,37.7 mmol) and Pd(OH)₂ (0.5 g) in MeOH was stirred at about 50° C. underH₂ atmosphere (50 psi) overnight. Then the mixture was filtrated throughCelite©, and the filtrate was concentrated. The crude product waspurified by flash chromatography to afford 6.3 g of the crude productwhich was recrystallized in a mixture of MTBE (15 mL) and HCl/MeOH (5mL) to provide (R)-2-(piperidin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one(HCl salt) as a solid (2.1 g, 21%): ¹H NMR (MeOD) 7.95 (d, J=8, 1H),7.51-7.47 (m, 1H), 7.38-7.34 (m, 1H), 7.29 (d, J=7.6, 1H), 4.86-4.80 (m,1H), 3.61-3.58 (m, 2H), 3.39-3.35 (m, 2H), 3.28-3.22 (m, 1H), 3.03-2.95(m, 3H), 2.12-1.87 (m, 4H); LC/MS (Table 1, Method d) R_(t)=2.05 min; MSm/z: 231 (M+H)⁺.

Step E:(R)-2-(1-(Methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)-1-tosyl-1H-indole-7-carbonitrile

A mixture of4-fluoro-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-tosyl-1H-indole-7-carbonitrile(318 mg, 0.672 mmol, Preparation #27),(R)-2-(piperidin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one hydrochloride(179 mg, 0.672 mmol) and TEA (0.374 mL, 2.69 mmol) in DMSO (4 mL) wereheated in a microwave at about 120° C. for about 20 min. The reactionwas heated in a microwave at about 120° C. for an additional 30 min.Water (50 mL) was added and extracted into DCM. The solution was washedwith brine and passed through a phase separator to remove residualwater. The organics were concentrated and chromatographed on silica toeluting with a gradient of 0-100% EtOAc/hexane to provide crude(R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)-1-tosyl-1-indole-7-carbonitrile(110 mg, 24%). The material was used without further purification.

Step F:(R)-2-(1-(Methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide

A mixture of Cs₂CO₃ (51.9 mg, 0.159 mmol) and(R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)-1-tosyl-1H-indole-7-carbonitrile(109 mg, 0.159 mmol) in THF (2 mL) and MeOH (1.000 mL) were stirred atrt overnight. The mixture was diluted with water (15 mL) and stirred forabout 20 min. The precipitate was collected by filtration and the filtercake was washed with water. The filter cake was dissolved in t-butanol(1 mL) and DMSO (0.500 mL) was added NaOH (0.956 mL, 1.91 mmol) andhydrogen peroxide (0.444 mL, 4.30 mmol). The mixture was stirred forabout 20 min at rt and saturated NH₄Cl (1 mL) was added. The mixture wasdiluted with water (15 mL) and stirred for about 15 min. The solids werecollected by filtration washing several times with water and dried undervacuum. The resulting solids were purified by prep-HPLC (Table 1, Methodap). The samples were returned and dissolved in DCM. The organics werecombined and washed with saturated sodium bicarbonate, filtered througha Biotage phase separator, and concentrated. The residue was furtherdried in a vacuum oven at about 50° C. for about 48 h to afford(R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide(30 mg, 34%): LC/MS (Table 1, Method f) R_(t)=1.63 min; MS m/z: 548(M+H)⁺. (Btk IC₅₀=A)

Example #13A*:(R)—N-(1-(7-Carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)piperidin-3-yl)thiazole-2-carboxamide

Step A: (R)-tert-Butyl3-(thiazole-2-carboxamido)piperidine-1-carboxylate

To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (2 g,9.99 mmol) and thiazole-2-carboxylic acid (1.29 g, 9.99 mmol) in DCM (40mL) was added HATU (4.85, 12.5 mmol) and DIEA (3.87 g, 29.9 mmol) andthe mixture was stirred at rt overnight. Then the mixture was pouredinto water and extracted with DCM (3×80 mL). The combined organic layerswere washed with saturated aqueous NaHCO₃ (80 mL) and brine (80 mL), anddried over Na₂SO₄. The solvent was concentrated under reduced pressureto afford the crude product, which was purified by column chromatographyon silica gel to provide (R)-tert-butyl3-(thiazole-2-carboxamido)piperidine-1-carboxylate (2.2 g, 71%): ¹H NMR(CDCl3) δ 1.45 (s, 9H), 1.78-1.73 (m, 2H), 1.94-1.91 (m, 1H), 2.80 (s,2H), 3.42 (br, 2H), 3.66 (d, J=13.2 Hz, 1H), 4.11 (s, 1H), 7.36 (br,1H), 7.57 (t, J=3.2 Hz, 1H), 7.84 (t, J=3.2 Hz, 1H).

Step B: (R)—N-(Piperidin-3-yl)thiazole-2-carboxamide

To a solution of (R)-tert-butyl3-(thiazole-2-carboxamido)piperidine-1-carboxylate (1.9 g, 6.1 mmol) inEtOAc (20 mL) was added HCl/EtOAc (20 mL) dropwise at about 0° C., thenthe reaction was stirred at rt for about 3 h. The mixture was filteredand the filter cake was hygroscopic. The filter cake was dissolved intowater and saturated aqueous NaHCO₃ solution. The mixture was extractedwith DCM (3×50 mL) and the combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to provide(R)—N-(piperidin-3-yl)thiazole-2-carboxamide (1.2 g, 5.68 mmol, 93%): ¹HNMR (CDCl3) δ 1.79-1.66 (m, 3H), 1.92-1.86 (m, 1H), 2.04 (s, 1H),2.87-2.70 (m, 3H), 3.15-2.88 (m, 1H), 4.12-4.06 (m, 1H), 7.54-7.53 (m,2H), 7.84 (t, J=2.8 Hz, 1H).

Step C:(R)—N-(1-(7-Cyano-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-tosyl-1H-indol-4-yl)piperidin-3-yl)thiazole-2-carboxamide

A mixture of4-fluoro-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-tosyl-1H-indole-7-carbonitrile(200 mg, 0.422 mmol, Preparation #27), (R)—N-(piperidin-3-yl)thiazole-2-carboxamide (178 mg, 0.842 mmol) and TEA (170 mg, 1.680 mmol)in DMSO (2 mL) was heated under microwave condition at about 120° C. forabout 1 h. Water (10 mL) was added to the mixture and extracted with DCM(3×20 mL). The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crudeproduct which was purified by Prep-TLC (DCM:MeOH=75:1) to provide(R)—N-(1-(7-cyano-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-tosyl-1H-indol-4-yl)piperidin-3-yl)thiazole-2-carboxamide(20 mg, 7%): LC/MS (Table 1, Method m) R_(t)=2.24 min; MS m/z: 665(M+H)⁺.

Step D:(R)—N-(1-(7-Carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)piperidin-3-yl)thiazole-2-carboxamide

A mixture of(R)—N-(1-(7-cyano-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-tosyl-1H-indol-4-yl)piperidin-3-yl)thiazole-2-carboxamide(76 mg, 0.114 mmol), NaOH (54.9 mg, 1.37 mmol) and 30% H₂O₂ (350 mg,3.09 mmol) in the mixture of DMSO (1 mL) and n-butanol (2 mL) wasstirred at rt for about 24 h. Then saturated aqueous NH₄Cl (2 mL) wasadded and diluted with water (30 mL) and stirred for 30 min. The solidwas collected by filtration and washed several times with water and thecrude product was purified by Prep-TLC (50:1 DCM/MeOH) to provide(R)—N-(1-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)piperidin-3-yl)thiazole-2-carboxamide(32 mg, 53%): LC/MS (Table 1, Method d) R_(t)=2.90 min; MS m/z: 529(M+H)⁺. (Btk IC₅₀=A)

Example #14:2-(1-Methyl-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-benzo[d]imidazole-7-carboxamide

Step A:3-(3-(7-Bromobenzo[c][1,2,5]thiadiazol-4-yl)-2-methylphenyl)quinazolin-4(3H)-one

To a solution of 4,7-dibromobenzo[c][1,2,5]thiadiazole (1.029 g, 3.5mmol) and3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one(1.141 g, 3.15 mmol, WO 2011159857) in the mixture of toluene (40 mL),MeOH (10 mL) and water (10 mL) were added Na₂CO₃ (0.742 g, 7.00 mmol)and Pd(PPh₃)₄ (0.081 g, 0.070 mmol). The mixture was heated to about100° C. for 24 h. The resulting solution was cooled to rt and dilutedwith EtOAc, washed with water and brine, dried over Na₂SO₄, filtered andconcentrated to give a crude product, which was purified by columnchromatography on silica gel (eluted with Pet ether:EtOAc=5:1 to 1:1) toafford3-(3-(7-bromobenzo[c][1,2,5]thiadiazol-4-yl)-2-methylphenyl)quinazolin-4(3H)-one(1.0 g, 64%): ¹H NMR (CDCl₃) δ 8.40-8.38 (d, J=8.0 Hz, 1H), 8.13 (s,1H), 7.95-7.93 (d, J=7.6 Hz, 1H), 7.82-7.80 (m, 2H), 7.58-7.56 (m, 1H),7.51-7.46 (m, 3H), 7.41-7.39 (t, J=4.8 Hz, 1H), 1.95 (s, 3H).

Step B:7-(2-Methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)benzo[c][1,2,5]thiadiazole-4-carbonitrile

To a solution of3-(3-(7-bromobenzo[c][1,2,5]thiadiazol-4-yl)-2-methylphenyl)quinazolin-4(3H)-one(0.449 g, 1 mmol) in DMF (12 mL) were added Zn (CN)₂ (0.076 g, 0.650mmol) and Pd(PPh₃)₄ (0.046 g, 0.040 mmol). The mixture was heated toabout 160° C. for about 15 min under N₂ atmosphere in a microwavereactor. The resulting solution was diluted with EtOAc, and washed withbrine (4×). The organic phase was dried over Na₂SO₄, filtered andconcentrated to give a crude product, which was purified by columnchromatography on silica gel (eluted with Pet ether:EtOAc=5:1 to 1:1) toprovide7-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)benzo[c][1,2,5]thiadiazole-4-carbonitrile(0.3 g, 76%): ¹H NMR (CDCl₃) δ 8.33-8.03 (d, J=8.0 Hz, 1H), 8.10-8.06(t, J=7.2 Hz, 2H), 7.77-7.74 (m, 2H), 7.63-7.61 (t, J=7.2 Hz, 1H),7.53-7.45 (m, 3H), 7.39-7.37 (d, J=7.2 Hz, 1H), 1.90 (s, 3H).

Step C:2,3-Diamino-2′-methyl-3′-(4-oxoquinazolin-3(4H)-yl)-[1,1′-biphenyl]-4-carbonitrile

To a solution of2,3-diamino-2′-methyl-3′-(4-oxoquinazolin-3(4H)-yl)-[1,1′-biphenyl]-4-carbonitrile(0.53 mg, 1.34 mmol) in AcOH (50 mL) was added zinc (1.75 g, 26.8 mmol),the mixture was heated to about 120° C. for about 2 h. The solvent wasconcentrated and the residue was taken up into EtOAc, washed withsaturated aqueous NaHCO₃ solution and brine. The organic phase was driedover Na₂SO₄, filtered and concentrated to give a crude product, whichwas purified by column chromatography on silica gel (eluted with Petether:EtOAc=1:1 to 0:1) to provide2,3-diamino-2′-methyl-3′-(4-oxoquinazolin-3(4H)-yl)-[1,1′-biphenyl]-4-carbonitrile(0.4 g, 81%): LC/MS (Table 1, Method 1) R_(t)=1.33 min; MS m/z: 368(M+H)⁺.

Step D:2-(1-Methyl-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-benzo[d]imidazole-7-carbonitrile

To a solution of2,3-diamino-2′-methyl-3′-(4-oxoquinazolin-3(4H)-yl)-[1,1′-biphenyl]-4-carbonitrile(400 mg, 1.09 mmol) in DMF (15 mL) were added1-methyl-1H-pyrazole-4-carbaldehyde (240 mg, 2.18 mmol) and TMSCl (0.417mL, 3.27 mmol). The mixture was heated to about 100° C. for about 30 minin a microwave reactor. The resulting solution was diluted with EtOAc,and washed with brine (4×). The organic phase was dried over Na₂SO₄,filtered and concentrated to give a crude product, which was purified bycolumn chromatography on silica gel (eluted with Pet ether:EtOAc=1:1then EtOAc:MeOH=50:1) to provide2-(1-methyl-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-benzo[d]imidazole-7-carbonitrile(200 mg, 40%): LC/MS (Table 1, Method m) R_(t)=1.78 min; MS m/z: 458(M+H)⁺.

Step E:2-(1-Methyl-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-benzo[d]imidazole-7-carboxamide

To a solution of2-(1-methyl-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-benzo[d]imidazole-7-carbonitrile(278 mg, 0.608 mmol) in the mixture of butanol (6 mL) and DMSO (3 mL)were added NaOH (292 mg, 7.29 mmol) and H₂O₂ (1.68 mL, 16.4 mmol). Themixture was stirred for about 24 h at about 25° C. The resultingsolution was quenched with saturated aqueous NH₄Cl solution, extractedwith EtOAc. The organic phase was dried over Na₂SO₄, filtered andconcentrated to give a crude product, which was purified by prep-HPLC(Table 1, Method n) to provide2-(1-methyl-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-benzo[d]imidazole-7-carboxamide(140 mg, 48%): LCMS (Table 1, Method d) R_(t)=2.53 min; MS m/z: 476(M+H)⁺. (Btk IC₅₀=B)

Example #15: 4-(3-Acrylamidophenyl)-1H-indazole-7-carboxamide

Step A: 3-(7-Carbamoyl-1H-indol-4-yl)benzoic acid

A mixture of 4-bromo-1H-indole-7-carboxamide (0.5 g, 2.091 mmol,Preparation #2), (3-(methoxycarbonyl)phenyl)boronic acid (0.565 g, 3.14mmol), sodium carbonate (2.61 mL, 5.23 mmol) in DME (10.00 mL) wasdegassed and purged with nitrogen for about 5 min, thentetrakis(triphenylphosphine)palladium(0) (0.121 g, 0.105 mmol) wasadded. The reaction vessel was sealed and heated with microwave (BiotageInitiator) at about 110° C. for about 45 min. The mixture was cooled tort, followed by addition of about 50 mL of water. The precipitate isfiltered, air-dried and used without further purification. This crudewas then dissolved in THF (25 mL) and treated with lithium hydroxide(0.250 g, 10.46 mmol) solution in water (25 mL). The reaction mixturewas stirred at rt overnight. THF was removed and the aqueous layer wasextracted with DCM to remove triphenylphosphine oxide. The aqueous phasewas then acidified with 1N HCl solution to about pH 2. The precipitatewas filtered and dried to give 0.58 g of crude3-(7-carbamoyl-1H-indol-4-yl)benzoic acid as a solid. LC/MS (Table 1,Method g) R_(t)=1.37 min; MS m/z 281 (M+H)⁺.

Step B: 4-(3-((Cyanomethyl)carbamoyl)phenyl)-1H-indole-7-carboxamide

A mixture of 3-(7-carbamoyl-1H-indol-4-yl)benzoic acid (0.1 g, 0.357mmol), TBTU (0.172 g, 0.535 mmol) and DIEA (0.249 mL, 1.43 mmol) in DMF(5.0 mL) was stirred at rt for about 5 min, followed by addition of2-aminoacetonitrile, hydrochloric acid (0.040 g, 0.43 mmol). Thereaction mixture was stirred at the same temperature overnight. Waterwas added and the aqueous phase was extracted with EtOAc. Organic layerwas washed with brine, dried over magnesium sulfate and filtered. Thefiltrate was dried and the crude was purified by prep HPLC (Table 1,Method i) to give cyanomethyl)carbamoyl)phenyl)-1H-indole-7-carboxamide(0.065 g, 57%) as a solid. LC/MS (Table 1, Method g) R_(t)=1.30 min; MSm/z 319 (M+H)⁺ (Btk IC₅₀=C) Example #16:4-(3-Amino-2-methylphenyl)-1H-indole-7-carboxamide

A mixture of 4-bromo-1H-indole-7-carboxamide (1.28 g, 5.35 mmol,Preparation #2),2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.37 g,5.89 mmol, Combi-Blocks), Na₂CO₃ (1.70 g, 16.06 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.392 g,0.535 mmol) in THF (41.8 mL), MeOH (5.86 Ll), and water (5.86 mL) wasstirred at about 70° C. for about 16 h under a nitrogen atmosphere. Themixture was filtered through Celite® and concentrated under reducedpressure. The crude product was purified by silica gel column with 0-10%MeOH in DCM to provide the crude product. The residue was trituratedwith DCM (2× with sonication for about 5 min), filtered, was washed withDCM and dried under reduced pressure to provide4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide (0.86 g, 61%): LC/MS(Table 1, Method g) R_(t)=1.03 min; MS m/z: 266 (M+H)⁺. (Btk IC₅₀=C)

Example #17:4-(3-Acrylamido-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

To a solution of4-(3-amino-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (3.0g, 11.3 mmol, Example #2) and TEA (3.14 mL, 22.5 mmol) in THF (113 mL)was slowly added acryloyl chloride (1.01 mL, 12.4 mmol) at 0° C. Thereaction was stirred at about 0° C. for about 20 min. The mixture wasconcentrated under reduced pressure and water (100 mL) was added and thesuspension was sonicated for 30 min, filtered, washed with water (100mL), ether (100 mL) and dried to give4-(3-acrylamido-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide(3.05 g, 85%): LC/MS (Table 1, Method f) R_(t)=1.27 min; MS m/z: 321(M+H)⁺. (Btk IC₅₀=A)

Example #18: 4-(3-Acrylamidophenyl)-1H-indazole-7-carboxamide

Step A: Methyl 2-amino-4-chloro-3-methylbenzoate

To a mixture of 2-amino-4-chloro-3-methylbenzoic acid (5.0 g, 26.9 mmol,Enamine) and cesium carbonate (13.2 g, 40.4 mmol) in DMF (100 mL) wasadded iodomethane (1.77 mL, 28.3 mmol). The mixture was then stirred atrt for about 16 h. Water was added and extracted with EtOAc. The organiclayer was washed with brine, dried over magnesium sulfate and filtered.The filtrate was concentrated and purified by chromatography on silicagel (5-60% EtOAc in heptane) to provide methyl2-amino-4-chloro-3-methylbenzoate (4.48 g) as a solid. LC/MS (Table 1,Method g) R_(t)=1.74 min; MS m/z 200 (M+H)⁺.

Step B: Methyl 4-chloro-1H-indazole-7-carboxylate

To a solution of methyl 2-amino-4-chloro-3-methylbenzoate (4.5 g, 22.5mmol) in CHCl₃ (100 mL) was added acetic anhydride (4.89 mL, 51.8 mmol).The mixture was then stirred at rt for about 2 h, followed by additionof isopentyl nitrite (6.68 mL, 49.6 mmol) and potassium acetate (0.664g, 6.76 mmol). The reaction mixture was heated at refluxed for about 18h. The reaction was diluted with DCM and washed with saturated sodiumbicarbonate and dried over magnesium sulfate. The filtrate isconcentrate to provide crude methyl 4-chloro-1H-indazole-7-carboxylate(4.46 g): LC/MS (Table 1, Method g) R_(t)=1.47 min; MS m/z 211 (M+H)⁺.

Step C: 4-Chloro-1H-indazole-7-carboxamide

To a suspension of methyl 4-chloro-1H-indazole-7-carboxylate (4.3 g,20.4 mmol) in 1,4-dioxane (75 mL) was added a solution of KOH (1.69 g,26.5 mmol) in water (75 mL). The reaction mixture was then stirred at rtfor about 16 h to give a clear solution. Solvent was removed and theresidue was treated with 1N HCl to precipitate the crude acid, which wasused without further purification. A mixture of this crude acid (0.5 g,2.54 mmol), N-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.731 g, 3.82 mmol) and HOBt (0.584 g, 3.82 mmol) in DMF(15 mL) was stirred at rt for about 60 min, then ammonia (0.5 N solutionin 1,4-dioxane, 50.9 mL, 25.4 mmol) was added. The reaction mixture wasstirred at rt for about 6 h. The suspension was filtered and washed withEtOAc. The filtrate was concentrated and treated with water. Theprecipitate was filtered, washed with water and air-dried to provide4-chloro-1H-indazole-7-carboxamide (0.43 g) as a solid; LC/MS (Table 1,Method g) R_(t)=1.00 min; MS m/z 196 (M+H)⁺.

Step D: 4-(3-Aminophenyl)-1H-indazole-7-carboxamide

A suspension of 4-chloro-1H-indazole-7-carboxamide (0.15 g, 0.767 mmol),tert-butyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (0.367g, 1.15 mmol), cesium carbonate (0.75 g, 2.3 mmol) in DME (4.0 mL) andwater (2.0 mL) was degassed and purged with nitrogen for 5 min. Thentris(dibenzylideneacetone)dipalladium(0) (0.07 g, 0.077 mmol) and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.037 g, 0.077mmol) were added. The reaction vessel was sealed and heated usingBiotage Initiator at about 140° C. for about 30 min. The mixture wascooled to rt and filtered through a pad of Celite®. The filtrate waspartitioned between water and EtOAc. Organic layer was washed withbrine, dried over magnesium sulfate and filtered. The filtrate wasconcentrated and purified by chromatography on silica gel (30-100%EtOAc/heptane). This product was then dissolved in DCM (2 mL) andtreated with TFA (5 mL, 64.9 mmol). The reaction mixture was stirred atrt overnight. Excess TFA and solvent were removed to provide crude4-(3-aminophenyl)-1H-indazole-7-carboxamide, trifluoroacetic acid (0.195g) as a solid. LC/MS (Table 1, Method g) R_(t)=0.25 min; MS m/z 253(M+H)⁺.

Step E: 4-(3-Acrylamidophenyl)-1H-indazole-7-carboxamide

A suspension of 4-(3-aminophenyl)-1H-indazole-7-carboxamide, TFA (0.1 g,0.27 mmol), DIEA (0.143 mL, 0.819 mmol) in THF (2.5 mL) was cooled in anice bath and acryloyl chloride (0.026 mL, 0.31 mmol) is added slowly.After 30 min, the reaction was treated with MeOH and stirred for about 5min. Solvent was then removed under vacuum and the residue wastriturated with DCM to provide4-(3-acrylamidophenyl)-1H-indazole-7-carboxamide (56 mg) as a solid: ¹HNMR (d-DMSO-d6) δ 13.17 (s, 1H) 10.34 (s, 1H) 8.28 (s, 1H) 8.21 (s, 1H)8.17 (s, 1H) 8.00 (d, J=7.48 Hz, 1H) 7.73 (d, J=7.70 Hz, 1H)7.40-7.59(m, 3H)7.30 (d, J=7.59 Hz, 1H)6.39-6.58 ((m, 1H)6.17-6.36 ((m, 1H)5.60-5.97 (m, 1H). (Btk IC₅₀=A)

Example #19: 4-(3-Acrylamidophenyl)-1H-indazole-7-carboxamide

Step A: Methyl4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate

To a solution of diisopropylamine (1.45 mL 10.1 mmol) and anhydrous THF(30 mL), a solution of t-BuLi (11 mL, 11.7 mmol) in pentane was added atabout −78° C. under nitrogen atmosphere reaction mixture was stirred forabout 30 min. Then a solution of methyl4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate (3g, 7.81 mmol, Preparation #10, step A) in anhydrous THF (10 mL) wasadded at about −78° C. After about 2 h, a solution of iodomethane (2.216g, 15.61 mmol) in anhydrous THF (10 mL) was added at about −78° C. Themixture continued to stir for about 2 h at about −78° C. The reactionmixture was quenched with aqueous NH₄Cl, extracted with EtOAc (500mL×3). The organic phase was dried over Na₂SO₄, concentrated underreduced pressure, and the residue was purified by prep-HPLC (Table 1,Method ao) to provide methyl4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate(1 g, 32%) as a solid: ¹H NMR (CDCl₃) δ 7.51-7.49 (d, J=8.0, 1H),7.39-7.37 (d, J=8, 1H), 6.55 (s, 1H), 5.77 (s, 2H), 4.06 (s, 3H),3.31-3.27 (m, 2H), 2.60 (s, 3H), 0.87-0.83 (m, 2H), 0.00 (s, 9H).

Step B:4-Bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylicacid

To a solution of methyl4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylate(0.6 g, 1.5 mmol) in MeOH (3 mL), THF (6 mL) and water (3 mL), LiOH(0.361 g, 15.1 mmol) was added and the reaction mixture was heated toabout 45° C. for about 3 h. The reaction mixture was adjusted to pH<3 bythe addition of 1N HCl, then extracted with EtOAc (300 mL×3), and theorganic phase was concentrated under reduced pressure to provide4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylicacid (0.5 g, 86%) as a solid: ¹H NMR (DMSO-d6) δ 13.32 (s, 1H),7.53-7.42 (m, 2H), 6.56 (s, 1H), 5.86 (s, 2H), 3.36-3.32 (m, 2H), 2.63(s, 3H), 0.90-0.82 (m, 2H), 0.00 (s, 9H).

Step C:4-Bromo-2-methyl-1-((2-(trimethysilyl)ethoxy)methyl)-1H-indole-7-carboxamide

To a solution of4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxylicacid (0.5 g, 1.30 mmol) in THF (10 mL) and DCM (12 mL), HOBt (0.299 g,1.95 mmol) and EDCI (0.374 g, 1.95 mmol) were added at about 0° C. Thenthe reaction mixture was stirred for about 1 hour at rt, then bubbledwith NH₃ gas for about 20 min, and stirring continued overnight at rt.Aqueous NaHCO₃ was added and the mixture was extracted with EtOAc (200mL×3), and the organic phase was dried over Na₂SO₄, concentrated underreduced pressure to provide4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide(0.45 g, 90%) as a solid: ¹H NMR (DMSO-d6) δ 8.10 (s, 1H), 7.67 (s, 1H),7.36-7.34 (d, J=8, 1H), 7.20-7.18 (d, J=8, 1H), 6.46 (s, 1H), 5.74 (s,2H), 3.46-3.38 (m, 2H), 2.56 (s, 3H), 0.90-0.83 (m, 2H), 0.00 (s, 9H).

Step D: 4-Bromo-2-methyl-1H-indole-7-carboxamide

To a solution of4-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide(350 mg, 0.913 mmol) in THF (15 mL) was added TBAF (2.4 g, 9.13 mmol)and ethane-1,2-diamine (1.1 g, 18.3 mmol). The mixture was refluxedovernight. The reaction mixture was concentrated under reduced pressureand the residue was purified by silica gel column to provide4-bromo-2-methyl-1H-indole-7-carboxamide (180 mg, 78%) as a solid: ¹HNMR (DMSO-d6) δ 11.18 (s, 1H), 8.05 (s, 1H), 7.48-7.42 (m, 2H),7.20-7.18 (d, J=8, 1H), 6.14 (s, 1H), 2.41 (s, 3H).

Step E: 4-(3-Aminophenyl)-2-methyl-1H-indole-7-carboxamide

To a solution of 4-bromo-2-methyl-1H-indole-7-carboxamide (180 mg, 0.711mmol) in THF (8 mL) and water (4 mL) and MeOH (4 mL) was added3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (187 mg, 0.853mmol), Pd(dppf)Cl₂ (104 mg, 0.142 mmol) and Na₂CO₃ (226 mg, 2.13 mmol),and the solution was heated at about 90° C. for about 2 h. The reactionmixture was concentrated under reduced pressure and purified by silicagel column to provide 4-(3-aminophenyl)-2-methyl-1H-indole-7-carboxamide(80 mg, 42%) as a solid: ¹H NMR (MeOD) δ 10.92 (s, 1H), 7.99 (s, 1H),7.66-7.63 (d, J=12, 2H), 7.61 (s, 1H), 7.13-7.09 (m, 1H), 6.99-6.97 (d,J=8, 1H), 6.88 (s, 1H), 6.78-6.73 (m, 2H), 6.58-6.56 (d, J=8, 1H), 6.29(s, 1H), 2.42 (s, 3H).

Step F: 4-(3-Acrylamidophenyl)-2-methyl-1H-indole-7-carboxamide

To a solution of 4-(3-aminophenyl)-2-methyl-1H-indole-7-carboxamide (80mg, 0.302 mmol) in DCM (6 mL), acryloyl chloride (40.9 mg, 0.452 mmol)and DIEA (0.105 mL, 0.603 mmol) were added at about 0° C. The mixturewas stirred for about 1 hour at rt. The reaction mixture wasconcentrated under reduced pressure and the residue was purified byprep-HPLC (Table 1, Method an) to give4-(3-acrylamidophenyl)-2-methyl-1H-indole-7-carboxamide (10 mg, 11%) asa solid: LC/MS (Table 1, Method j) R_(t)=2.07 min; MS m/z: 320 (M+H)⁺.(Btk IC₅₀=A) Example #20:4-(3-Acrylamidophenyl)-2-ethyl-1H-indole-7-carboxamide

Step A: 4-Bromo-2-iodo-1H-indole-7-carboxamide

To a solution of4-bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide((1.5 g, 3.03 mmol, Preparation #24) in THF (20 mL), TBAF (15.84 g, 60.6mmol) and ethane-1,2-diamine (1.82 g, 30.3 mmol) were added, and thesolution was heated at reflux overnight. The solution was concentratedunder reduced pressure and water (30 mL) and EtOAc (30 mL) were added,and the organic phase was dried and concentrated under reduced pressure.The residue was purified by column chromatography (Pet ether:EtOAc=10: 1to 1:1) to provide 4-bromo-2-iodo-1H-indole-7-carboxamide (700 mg, 63%):LC/MS (Table 1, Method k) R_(t)=1.91 min; MS m/z: 367 (M+H)⁺.

Step B: 4-Bromo-2-vinyl-1H-indole-7-carboxamide

To a solution of 4-bromo-2-iodo-1H-indole-7-carboxamide (0.630 g, 1.726mmol) in 1.4-dioxane (4.5 mL) and water (0.5 mL), CsF (0.787 g, 5.18mmol), Pd(PPh₃)₂C₁₂ (0.242 g, 0.345 mmol) and potassiumtrifluoro(vinyl)borate (254 mg, 1.899 mmol) were added. The reactionmixture was heated to about 90° C. for about 2 h under N₂ atmosphere.The mixture was concentrated under reduced pressure, and the residue waspurified by column chromatography to provide4-bromo-2-vinyl-1H-indole-7-carboxamide (0.140 g, 31%): ¹H NMR (CDCl3) δ10.36 (s, 1H), 7.2-7.12 (m, 2H), 6.72-6.65 (m, 1H), 6.50 (s, 1H),6.25-5.78 (m, 2H), 5.69 (d, J=17.6, 1H), 5.33 (d, J=10.8, 1H).

Step C: 4-(3-Aminophenyl)-2-vinyl-1H-indole-7-carboxamide

To a solution of 4-bromo-2-vinyl-1H-indole-7-carboxamide (0.12 g, 0.45mmol) in THF (10 mL), water (5 mL) and MeOH (5 mL),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (119 mg, 0.543mmol), PdCl₂(dppf) (66.2 mg, 0.091 mmol) and Na₂CO₃ (144 mg, 1.358 mmol)were added. The reaction mixture was heated at about 90° C. for about 2h. The mixture was concentrated under reduced pressure and the residuewas purified by column chromatography on silica gel to provide4-(3-aminophenyl)-2-vinyl-1H-indole-7-carboxamide (80 mg, 75%): LC/MS(Table 1, Method 1) R_(t)=1.06 min; MS m/z: 278 (M+H)⁺.

Step C: 4-(3-Aminophenyl)-2-ethyl-1H-indole-7-carboxamide

To a solution of 4-(3-aminophenyl)-2-vinyl-1H-indole-7-carboxamide (46mg, 0.116 mmol) in THF (10 mL), Pd/C (10 mg, 0.094 mmol) was added. Themixture was stirred for about 1.5 h at rt. The mixture was filteredthrough a pad of Celite©, and the filtrate was concentrated underreduced pressure to provide4-(3-aminophenyl)-2-ethyl-1H-indole-7-carboxamide (40 mg, 70%), whichwas used to next step directly: LC/MS (Table 1, Method 1) R_(t)=1.21min; MS m/z: 280 (M+H)⁺.

Step D:4-(3-Acrylamidophenyl)-2-ethyl-1H-indole-7-carboxamide

To a solution of 4-(3-aminophenyl)-2-ethyl-1H-indole-7-carboxamide (20mg, 0.072 mmol) in DCM (15 mL), TEA (29 mg, 0.288 mmol) and acryloylchloride (13.05 mg, 0.144 mmol) were added at about 0° C. The solutionwas stirred overnight at rt. The solution was concentrated under reducedpressure, and the residue was purified by pre-HPLC (Table 1, Method am)to provide 4-(3-acrylamidophenyl)-2-ethyl-1H-indole-7-carboxamide (9 mg,38%): LC/MS (Table 1, Method d) R_(t)=2.91 min; MS m/z: 334 (M+H)⁺. (BtkIC₅₀=A)

Example #21:4-(3-Amino-2-methylphenyl)-2-(4,4-difluorocyclohex-1-enyl)-1H-indole-7-carboxamide

Step A:4-Bromo-2-(4,4-difluorocyclohex-1-en-1-yl)-1H-indole-7-carboxamide

A mixture of2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.267 g, 1.09 mmol, Syngene), 4-bromo-2-iodo-1H-indole-7-carboxamide(0.363 g, 0.995 mmol, Preparation #1), Na₂CO₃ (0.316 g, 2.98 mmol) inTHF (7 mL), MeOH (0.98 mL), and water (0.98 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.073 g,0.099 mmol). The mixture was bubbled with nitrogen and the vessel wassealed and heated at about 80° C. for about 4 h. The reaction was cooledto rt, filtered through Celite® and concentrated under reduced pressure.The residue was purified by silica gel column with EtOAc/hexanes(30-100%) to provide crude product which was further purified by silicagel column eluting with a gradient of 30-70% EtOAc/hexanes to provide4-bromo-2-(4,4-difluorocyclohex-1-en-1-yl)-1H-indole-7-carboxamide (0.25g, 71%): LC/MS (Table 1, Method f) R_(t)=1.82 min; MS m/z: 357 (M+H)⁺.

Step B:4-(3-Amino-2-methylphenyl)-2-(4,4-difluorocyclohex-1-enyl)-1H-indole-7-carboxamide

A mixture of4-bromo-2-(4,4-difluorocyclohex-1-enyl)-1H-indole-7-carboxamide (0.48 g,0.622 mmol),2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.203g, 0.870 mmol, Combi-Blocks), Na₂CO₃ (0.198 g, 1.865 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.045 g,0.062 mmol) in THF (5 mL), MeOH (0.700 mL), and water (0.700 mL) wasstirred at about 70° C. for about 16 h under a nitrogen atmosphere. Themixture was filtered through Celite® and concentrated under reducedpressure. The residue was passed through a silica gel column withEtOAc/heptane (50-75%) to provide the crude product. The crude productwas triturated with DCM (2× with sonication for about 5 min), filtered,washed with DCM and dried under reduced pressure to provide4-(3-amino-2-methylphenyl)-2-(4,4-difluorocyclohex-1-enyl)-1H-indole-7-carboxamide(134 mg, 57%): LC/MS (Table 1, Method f) R_(t)=1.36 min; MS m/z: 382(M+H)⁺. (Btk IC₅₀=A)

Example #22:4-(3-Acrylamidophenyl)-2-(2-ethoxyethyl)-1H-indole-7-carboxamide

Step A:(E)-4-Bromo-2-(2-ethoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide

Five reaction vessels were charged with a solution of4-bromo-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide(1 g, 2.02 mmol, Preparation #24) in toluene (100 mL) was added(E)-tributyl(2-ethoxyvinyl)stannane (1.09 g, 3.03 mmol), Pd(PPh₃)₂Cl₂(0.142 g, 0.202 mmol) and LiCl (0.428 g, 10.1 mmol). The mixtures wereheated at about 90° C. overnight under N₂ atmosphere. All five reactionmixtures were combined, concentrated under reduced pressure, and theresidue was purified by silica gel column to provide(E)-4-bromo-2-(2-ethoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide(2 g, 45%) as a yellow solid: ¹H NMR (DMSO-d6) δ 8.11 (s, 1H), 7.69 (s,1H), 7.37-7.35 (d, J=8, 1H), 7.17-7.15 (d, J=8, 1H), 6.96 (s, 1H),6.78-6.76 (d, J=8, 1H), 5.80-5.78 (d, J=8, 2H), 5.69-5.68 (d, J=4, 1H),4.24-4.08 (m, 2H), 3.42-3.36 (m, 2H), 1.43-1.34 (m, 3H), 0.86-0.82 (m,2H), 0.00 (s, 9H).

Step B:(E)-4-(3-Aminophenyl)-2-(2-ethoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide

To a solution of(E)-4-bromo-2-(2-ethoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide(1.5 g, 3.41 mmol) in THF (20 mL), water (10 mL) and MeOH (10 mL) wasadded 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.897 g,4.10 mmol), Pd(dppf)Cl₂ (0.5 g, 0.683 mmol) and Na₂CO₃ (1.085 g, 10.24mmol). The solution was heated at about 90° C. for about 2 h. Thereaction mixture was concentrated under reduced pressure and purified bysilica gel column to provide(E)-4-(3-aminophenyl)-2-(2-ethoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide(0.80 g, 52%): ¹H NMR (DMSO-d6) δ 8.06 (s, 1H), 7.62 (s, 1H), 7.30-7.22(m, 2H), 7.15 (s, 1H), 7.10-7.08 (d, J=8, 1H), 6.93 (s, 1H), 6.83-6.81(d, J=8, 1H), 6.68-6.65 (m, 2H), 5.82-5.80 (d, J=8, 2H), 5.67-5.66 (d,J=4, 1H), 5.28 (s, 2H), 4.18-4.06 (m, 2H), 3.43-3.37 (m, 2H), 1.39-1.33(m, 3H), 0.86-0.82 (m, 2H), 0.00 (s, 9H).

Step C:4-(3-Aminophenyl)-2-(2-ethoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide

Two reaction vessels were charged with a solution of(E)-4-(3-aminophenyl)-2-(2-ethoxyvinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide(400 mg, 0.886 mmol) in MeOH (60 mL), and Pd/C (400 mg, 10%). Themixtures were stirred for about 1 h at rt under H₂ (14 psi) atmosphere.The two reaction mixtures were combined, filtered and concentrated underreduced pressure to provide4-(3-aminophenyl)-2-(2-ethoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide(600 mg, 75%) as a solid, which was used directly for the next step: ¹HNMR (DMSO-d6) δ 8.05 (s, 1H), 7.61 (s, 1H), 7.32-7.31 (d, J=4, 1H),7.23-7.09 (m, 2H), 6.90 (s, 1H), 6.81-6.79 (d, J=8, 1H), 6.68-6.66 (d,J=8, 1H), 6.58 (s, 1H), 5.78 (s, 2H), 5.26 (s, 2H), 3.79-3.76 (m, 2H),3.55-3.52 (m, 2H), 3.45-3.41 (m, 2H), 3.15-3.12 (m, 2H), 1.26-1.15 (m,3H), 0.87-0.83 (m, 2H), 0.01 (s, 9H).

Step D: 4-(3-Aminophenyl)-2-(2-ethoxyethyl)-1H-indole-7-carboxamide

To a solution of4-(3-aminophenyl)-2-(2-ethoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carboxamide(500 mg, 1.10 mmol) in THF (20 mL) was added TBAF (2.88 g, 11.0 mmol)and ethane-1,2-diamine (1.33 g, 22.0 mmol). The mixture was stirred forabout 5 h at about 80° C. The reaction mixture was concentrated underreduced pressure, and the residue was purified by silica gel column toprovide 4-(3-aminophenyl)-2-(2-ethoxyethyl)-1H-indole-7-carboxamide (267mg, 75%) as a solid: ¹H NMR (DMSO-d6) δ 11.09 (s, 1H), 8.12 (s, 1H),7.76-7.74 (d, J=8, 1H), 7.46-7.44 (d, J=8, 1H), 7.24-7.19 (m, 1H),7.09-7.07 (d, J=8, 1H), 6.96 (s, 1H), 6.87-6.85 (d, J=8, 1H), 6.67-6.66(d, J=4, 1H), 6.45 (s, 1H), 5.25 (s, 2H), 3.76-3.73 (m, 2H), 3.59-3.54(m, 2H), 3.13-3.09 (m, 2H), 1.27-1.23 (m, 3H).

Step E: 4-(3-Acrylamidophenyl)-2-(2-ethoxyethyl)-1H-indole-7-carboxamide

Two reaction vessels were charged with a solution of4-(3-aminophenyl)-2-(2-ethoxyethyl)-1H-indole-7-carboxamide (60 mg,0.186 mmol) in DCM (2 mL). DIEA (0.065 mL, 0.371 mmol) and acryloylchloride (25.2 mg, 0.278 mmol) were added and the mixtures were stirredfor about 1 h at rt. The two reaction mixtures were combined,concentrated under reduced pressure, and the residue was purified byprep-HPLC (Table 1, Method w) to provide4-(3-acrylamidophenyl)-2-(2-ethoxyethyl)-1H-indole-7-carboxamide (21.6mg, 26.4%) as a solid: LC/MS (Table 1, Method d) R_(t)=2.95 min; MS m/z:378 (M−H)⁻. (Btk IC₅₀=A)

Example #23:4-(3-Acrylamidophenyl)-2-(2-hydroxyethyl)-1H-indole-7-carboxamide

Step A: 4-(3-Aminophenyl)-2-(2-hydroxyethyl)-1H-indole-7-carboxamide

Two reaction vessels were charged with a solution of4-(3-aminophenyl)-2-(2-ethoxyethyl)-1H-indole-7-carboxamide (100 mg,0.309 mmol, Example #22, Step D) in DCM (10 mL) was added dropwisetribromoborane (387 mg, 1.55 mmol) at about −78° C. The mixtures werestirred for about 2 h at about 0° C. The two reaction mixtures werecombined and aqueous NaHCO₃ was added and the mixture was extracted withDCM (100 mL×3). The organic phase was dried over Na₂SO₄, concentratedunder reduced pressure to give4-(3-aminophenyl)-2-(2-hydroxyethyl)-1H-indole-7-carboxamide (160 mg,88%) as a yellow solid: ¹H NMR (DMSO-d6) δ 10.96 (s, 1H), 8.04 (s, 1H),7.67-7.65 (d, J=8, 1H), 7.38-7.34 (d, J=16, 1H), 7.16-7.12 (m, 1H),7.01-6.99 (d, J=8, 1H), 6.91 (s, 1H), 6.81-6.80 (d, J=4, 1H), 6.62-6.59(d, J=12, 1H), 6.36 (s, 1H), 5.33 (s, 2H), 4.87 (s, 1H), 3.73-3.70 (m,2H), 2.96-2.93 (m, 2H).

Step B: 4-(3-Aminophenyl)-2-(2-hydroxyethyl)-1H-indole-7-carboxamide

To a solution of4-(3-aminophenyl)-2-(2-hydroxyethyl)-1H-indole-7-carboxamide (40 mg,0.135 mmol) in pyridine (4 mL) was added EDCI (31 mg, 0.163 mmol) andacrylic acid (9.8 mg, 0.135 mmol). The mixture was stirred for about 3 hat about 110° C. The reaction mixture was concentrated under reducedpressure and the residue was purified by prep-HPLC (Table 1, Method al)to provide4-(3-acrylamidophenyl)-2-(2-hydroxyethyl)-1H-indole-7-carboxamide (4.5mg, 10%) as a solid: LC/MS (Table 1, Method j) R_(t)=2.46 min; MS m/z:350 (M+H)⁺. (Btk IC₅₀=A)

Example #24:4-((1-Acryloylazetidin-3-yl)(methyl)amino)-1H-indole-7-carboxamide

Step A:tert-Butyl-3-((7-cyano-1H-indol-4-yl)amino)azetidine-1-carboxylate

In a 4 mL reaction vial, 4-bromo-1H-indole-7-carbonitrile (200 mg, 0.905mmol, Sinova),chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-amino-ethyl)phenyl]palladium(II)(9.03 mg, 0.011 mmol), anddicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine(6.07 mg, 0.011 mmol) were added. The solid mixture was evacuated andbackfilled with nitrogen. Lithium bis(trimethylsilyl)amide (2.17 mL,2.17 mmol) was added followed bytert-butyl-3-aminoazetidine-1-carboxylate (170 μl, 1.09 mmol). Thereaction mixture was heated at about 65° C. for about 2.5 h. Thereaction mixture was quenched with a few drops of 1N HCl and dilutedwith EtOAc (10 mL). The EtOAc layer was washed with a saturated aqueoussolution of NaHCO₃ and dried over MgSO₄, filtered and concentrated undervacuum. The crude material was purified via flash chromatography, usinga gradient of 5-40% EtOAc in heptane to givetert-butyl-3-((7-cyano-1H-indol-4-yl)amino)azetidine-1-carboxylate (160mg, 57%); LC/MS (Table 1, Method as) R_(t)=2.13 min.; MS m/z: 311(M−H)⁻.

Step B: tert-Butyl4-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-7-cyano-1H-indole-1-carboxylate

In a 100 mL round-bottomed flask, tert-butyl3-((7-cyano-1H-indol-4-yl)amino)azetidine-1-carboxylate (200 mg, 0.640mmol) in MeCN (5 mL) was added to give a brown solution. DMAP (15.6 mg,0.128 mmol) and BOC₂O (419 mg, 1.92 mmol) were added. Reaction mixturewas stirred for about 18 h at rt. Reaction mixture was diluted withwater (2 mL) and EtOAC (3 mL). The entire suspension was filtered andwashed with EtOAc (5 mL). The white precipitate collected was dried in avacuum oven at about 70° C. for about 2 h to give tert-Butyl4-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-7-cyano-1H-indole-1-carboxylate(154 mg, 58.3%). LC/MS (Table 1, Method as) R_(t)=2.54 min.; MS m/z: 411(M−H)⁻.

Step C:tert-Butyl-4-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-7-cyano-1H-indole-1-carboxylate

In a 4 mL reaction vial, sodium hydride (23.9 mg, 0.598 mmol, 60% dispin mineral oil) in DMF (1 mL) was added to give a white suspension.Reaction mixture was cooled to about 0° C. and tert-butyl4-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)-7-cyano-1H-indole-1-carboxylate(145 mg, 0.352 mmol) was added as a solution in DMF (4 mL). After about30 min, iodomethane (33 μl, 0.528 mmol) was added. Stirring wascontinued at 0° C. for about 1 h. The reaction was quenched with water(15 mL) and extracted with EtOAc (20 mL). The organic layer was driedover MgSO4, filtered and concentrated. The material was purified viaflash chromatography using a gradient of 0-25% EtOAc/heptane over 5 min,then held at 25% EtOAc/heptane for 5 min, to give crudetert-Butyl-4-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-7-cyano-1H-indole-1-carboxylate(148 mg, 71.1%); LC/MS (Table 1, Method as) R_(t)=2.71 min.; MS m/z: 427(M+H)⁺.

Step D: tert-Butyl3-((7-carbamoyl-1H-indol-4-yl)(methyl)amino)azetidine-1-carboxylate

To a solution of tert-butyl4-((1-(tert-butoxycarbonyl)azetidin-3-yl)(methyl)amino)-7-cyano-1H-indole-1-carboxylate(148 mg, 0.250 mmol) in ethanol (2 mL)/DMSO (0.500 mL) was addedhydrogen peroxide (0.515 mL, 5.04 mmol) and NaOH (1M, 0.515 mL, 0.515mmol). The reaction mixture was stirred at rt for about 2 h. To thereaction mixture was added water (5 mL) and the precipitate wascollected via filtration, washed with water (5 mL) and dried in a vacuumoven at about 70° C. for about 2 h to give tert-Butyl3-((7-carbamoyl-1H-indol-4-yl)(methyl)amino)azetidine-1-carboxylate (60mg, 52%); LC/MS (Table 1, Method as) R_(t)=1.97 min.; MS m/z: 345(M+H)⁺.

Step E: 4-(Azetidin-3-yl(methyl)amino)-1H-indole-7-carboxamide

In a 4 mL reaction vial, tert-butyl3-((7-carbamoyl-1H-indol-4-yl)(methyl)amino)azetidine-1-carboxylate (60mg, 0.129 mmol) in 1,4-dioxane (2 mL) was added to give an off-whitesolution. 4M HCl in dioxane (0.129 mL, 0.516 mmol) was added. Reactionwas stirred at rt for about 2 h. It was the warmed to about 50° C. forabout 2 h. Additional 4M HCl in dioxane (0.129 mL, 0.516 mmol) was addedand stirring was continued at about 50° C. for about 45 min. Reactionmixture was filtered and washed with DCM to give a precipitate. Theprecipitate was dissolved in water (2 mL) and basified with a few dropsof 5N aqueous NaOH solution. The aqueous layer was then extracted withDCM (2×7 mL) and EtOAC (2×8 mL). The organic layers were combined anddried over MgSO₄, filtered and concentrated to give4-(azetidin-3-yl(methyl)amino)-1H-indole-7-carboxamide (29 mg, 66%);LC/MS (Table 1, Method as) R_(t)=0.73 min.; MS m/z: 245 (M+H)⁺.

Step F:4-((1-Acryloylazetidin-3-yl)(methyl)amino)-1H-indole-7-carboxamide

A flask was charged with4-(azetidin-3-yl(methyl)amino)-1H-indole-7-carboxamide (28 mg, 0.083mmol) and N-ethyl-N-isopropylpropan-2-amine (65 μl, 0.373 mmol) in DCM(5 mL). The mixture was cooled to 0° C. on an ice-bath. Acryloylchloride (7.38 μl, 0.091 mmol) was added and the mixture stirred toabout 20 min. Reaction mixture was concentrated. The material waspurified via flash chromatography using a gradient of 1.0-3.3% MeOH/DCMover 7 min then held at 3.3% for 5 min to give4-((1-Acryloylazetidin-3-yl)(methyl)amino)-1H-indole-7-carboxamide (10.5mg, 43%); LC/MS (Table 1, Method a) R_(t)=1.31 min.; MS m/z: 299 (M+H)⁺.(Btk IC₅₀=A)

Example #25: 4-(1-Acryloylpiperidin-3-yl)-1H-indole-7-carboxamide

Step A: tert-Butyl3-(7-carbamoyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A 20 mL vial was charged with 4-bromo-1H-indole-7-carboxamide (300 mg,1.255 mmol), tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(466 mg, 1.506 mmol),(1,1-bis(diphenylphosphino)ferrocene)dichloropalladium (92 mg, 0.125mmol) and sodium carbonate (399 mg, 3.76 mmol). To the solid mixture wasadded THF (6 mL):MeOH (0.840 mL):Water (0.840 mL). The suspension wassparged with nitrogen for about 5 min. The reaction mixture was heatedat about 70° C. overnight. Reaction mixture was filtered over a pad ofCelite®, concentrated and purified by silica gel column (30-60%EtOAc/heptane) to give tert-butyl3-(7-carbamoyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (355mg, 83%); LC/MS (Table 1, Method as) R_(t)=2.14 min.; MS m/z: 340(M−H)⁻.

Step B: tert-Butyl 3-(7-carbamoyl-1H-indol-4-yl)piperidine-1-carboxylate

A flask was charged tert-butyl3-(7-carbamoyl-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (355mg, 1.04 mmol) and palladium (55.3 mg, 0.520 mmol). Ethyl acetate (10mL) was added under vacuum and the mixture was stirred under H₂ balloonat rt for about 5 h. The reaction mixture was filtered over a pad ofCelite® and washed with MeOH (20 mL) and EtOAc (30 mL). The filtrate wasconcentrated under reduced pressure to give tert-Butyl3-(7-carbamoyl-1H-indol-4-yl)piperidine-1-carboxylate (357 mg, 100%);LC/MS (Table 1, Method as) R_(t)=2.14 min.; MS m/z: 342 (M−H)⁻.

Step C: 4-(Piperidin-3-yl)-1H-indole-7-carboxamide

A flask was charged with Methanol (5 mL) and cooled to 0° C. Acetylchloride (0.828 mL, 11.6 mmol) was added drop wise, and the ice bath wasremoved. The mixture was stirred at rt for about 25 min. The solutionwas then added to tert-butyl3-(7-carbamoyl-1H-indol-4-yl)piperidine-1-carboxylate (100 mg, 0.291mmol) and the reaction mixture was stirred at rt for about 4 h. Themixture was concentrated under vacuum. The residue was dissolved inwater (10 mL) and washed with EtOAc (7 mL). The aqueous layer wasbasified with a few of drops of 50% w/w NaOH solution and extracted withEtOAC (12 mL). The EtOAc layer was dried over MgSO4, filtered andconcentrated to give 4-(Piperidin-3-yl)-1H-indole-7-carboxamide (40 mg,56%); the material was used crude in the next step without furthercharacterization.

Step D: 4-(1-Acryloylpiperidin-3-yl)-1H-indole-7-carboxamide

A flask was charged with 4-(piperidin-3-yl)-1H-indole-7-carboxamide (40mg, 0.164 mmol) and N-ethyl-N-isopropylpropan-2-amine (43 μL, 0.247mmol) in DCM (5 mL). The mixture was cooled to 0° C. Acryloyl chloride(14.69 μL, 0.181 mmol) was added and the mixture stirred for about 20min. Reaction mixture was concentrated. The material was purified bysilica gel column using a gradient of 1.0-5.5% MeOH/CH₂Cl2 over 10 min;to give 4-(1-Acryloylpiperidin-3-yl)-1H-indole-7-carboxamide (41 mg,84%); LC/MS (Table 1, Method a) R_(t)=1.53 min.; MS m/z: 298 (M+H)⁺.(Btk IC₅₀=B)

Example#26:4-(1-Acryloylpiperidin3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide

Step A: tert-Butyl3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A 20 mL vial was charged with4-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide (216 mg,0.677 mmol, Preparation #10), tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(251 mg, 0.812 mmol),(1,1-Bis(diphenylphosphino)ferrocene)dichloropalladium(1:1) complex withDCM (55.3 mg, 0.068 mmol) and sodium carbonate (215 mg, 2.03 mmol). Tothe solid mixture was added THF (3 mL):MeOH (0.420 mL):Water (0.420 mL).The suspension was sparged with N₂ for about 5 min. The reaction mixturewas heated at about 70° C. overnight. Reaction mixture was filtered overa pad of celite, concentrated and was purified by silica gel column(0-2% MeOH/DCM) to give tert-butyl3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate(227 mg, 80%); LC/MS (Table 1, Method as) R_(t)=2.09 min.; MS m/z: 422(M+H)⁺.

Step B: tert-butyl3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)piperidine-1-carboxylate

A flask was charged with tert-butyl3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate(227 mg, 0.539 mmol) and 10% palladium on carbon (28.7 mg, 0.027 mmol).Ethyl acetate (5 mL) was added under vacuum and the mixture was stirredunder H₂ balloon at rt for about 5 h. The reaction mixture was filteredover a pad of Celite© and washed with MeOH (20 mL) and EtOAc (30 mL).The filtrate was concentrated under reduced pressure to give the titlecompound (177 mg, 78%); LC/MS (Method as) R_(t)=2.08 min.; MS m/z: 424(M+H)⁺.

Step C:2-(1-Methyl-1H-pyrazol-4-yl)-4-(piperidin-3-yl)-1H-indole-7-carboxamide

A flask was charged with MeOH (2 mL) and cooled to 0° C. Acetyl chloride(0.151 mL, 2.12 mmol) was added drop wise, and the ice bath was removed.The mixture was stirred at rt for about 25 min. The solution was thenadded to tert-butyl3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)piperidine-1-carboxylate(30 mg, 0.071 mmol) and the reaction mixture was stirred at rtovernight. The mixture was concentrated under vacuum. The residue wasdissolved in water (3 mL) and washed with DCM (3 mL). The aqueous layerwas basified with a few drops of 5N NaOH to give a suspension, to whichwas added DCM. The DCM layer was separated. The aqueous layer formed aprecipitate which was collected via filtration and washed with a mixtureof DCM/EtOAC/MeOH (1:1:1) (6 mL). This filtrate was combined with theDCM layer and concentrated under vacuum to give2-(1-methyl-1H-pyrazol-4-yl)-4-(piperidin-3-yl)-1H-indole-7-carboxamide(18 mg, 79%); LC/MS (Table 1, Method as) R_(t)=1.03 min.; MS m/z: 324(M+H)⁺.

Step D: 4-(1-Acryloylpiperidin3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide

A flask was charged with2-(1-methyl-1H-pyrazol-4-yl)-4-(piperidin-3-yl)-1H-indole-7-carboxamide(18 mg, 0.056 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.044 mL,0.250 mmol) in DCM (5 mL). The mixture was cooled to 0° C. on anice-bath. Acryloyl chloride (4.97 μl, 0.061 mmol) was added and themixture stirred for about 20 min. Reaction mixture was concentrated. Thematerial was purified by silica gel column (2.0-6.5% MeOH/DCM) to give4-(1-acryloylpiperidin3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide (9 mg, 43%);LC/MS (Table 1, Method a) R_(t)=1.56 min.; MS m/z: 378 (M+H)⁺. (BtkIC₅₀=A)

Example #27: 4-((1-Acryloylazetidin-3-yl)oxy)-1H-indole-7-carboxamide

Step A: tert-butyl 3-(4-bromo-3-nitrophenoxy)azetidine-1-carboxylate

Cesium carbonate (2.038 g, 6.26 mmol) was added in DMF (12 mL) to give awhite suspension. Molecular sieves (4 Å, 8-12 mesh, beads, 100 mg)4-bromo-3-nitrophenol (1 g, 4.59 mmol) and tert-butyl3-((methylsulfonyl)oxy)azetidine-1-carboxylate (1.048 g, 4.17 mmol) wereadded, and the mixture was heated at about 85° C. for about 18 h. Thecrude mixture was partitioned between EtOAc (50 mL) and saturatedaqueous ammonium chloride solution (30 mL). The organic layer was washedby brine (30 mL), dried over sodium sulfate, filtered and concentratedto afford tert-butyl 3-(4-bromo-3-nitrophenoxy)azetidine-1-carboxylate(0.799 g, 2.14 mmol, 46.7% yield): LC/MS (Table 1, Method a) R_(t)=2.62min; MS m/z 373, 375 (M+H)⁺.

Step B: tert-butyl 3-((7-bromo-1H-indol-4-yl)oxy)azetidine-1-carboxylate

A 100 mL round-bottom flask was degassed with nitrogen and cooled toabout −70° C. in a dry-ice/acetone bath. A solution of vinylmagnesiumbromide in THF (1.0 M, 21.59 mL, 21.59 mmol) was added into the flask.Then a solution of tert-butyl3-(4-bromo-3-nitrophenoxy)azetidine-1-carboxylate (2.65 g, 5.40 mmol) in2-methyl-THF (18 mL) was added dropwise over 8 min, the mixture wasstirred at about −70° C. for about 1 h, and the reaction mixture wasquenched by saturated aqueous ammonium chloride solution (22 mL) atabout −60° C. The resulting mixture was warmed to rt and EtOAc (50 mL)and water (40 mL) were added. The layers were separated, the aqueouslayer was extracted with EtOAc (50 mL), the combined organic layers werewashed with brine (50 mL), dried over sodium sulfate, filtered andconcentrated to afford an orange oil, which was purified by silica gelchromatography eluting with a gradient of 0 to 40% EtOAc/heptane toafford tert-butyl 3-((7-bromo-1H-indol-4-yl)oxy)azetidine-1-carboxylate(0.87 g, 2.37 mmol, 43.9% yield): LC/MS (Table 1, Method a) R_(t)=2.52min; MS m/z 367, 369 (M+H)⁺.

Step C: tert-butyl 3-((7-cyano-1H-indol-4-yl)oxy)azetidine-1-carboxylate

In a 20 mL microwave reaction vial, tert-butyl3-((7-bromo-1H-indol-4-yl)oxy)azetidine-1-carboxylate (0.8 g, 2.178mmol), zinc cyanide (0.512 g, 4.36 mmol) and DMF (12 mL) were added togive a yellow suspension. The vial was degassed with nitrogen,tetrakis(triphenylphosphine)palladium(0) (0.755 g, 0.654 mmol) wasadded. The mixture was degassed with nitrogen, and then the reactionmixture was heated in a Biotage® microwave reactor at about 160° C. forabout 30 min (2 psi maximum pressure, 235 max watts). The resultingorange suspension was filtered through Celite®, washed with DMF (10 mL)and 2-methyl-THF (3×10 mL), the filtrate was concentrated in vacuo toremove most DMF, then it was partitioned between 2-methyl-THF (50 mL)and saturated aqueous ammonium chloride solution (50 mL). The organiclayer was washed with water (30 mL) and brine (30 mL), dried over sodiumsulfate, filtered and concentrated to afford an orange oil, which waspurified by silica gel chromatography eluting with a gradient of 0 to50% EtOAc/heptane to afford tert-butyl3-((7-cyano-1H-indol-4-yl)oxy)azetidine-1-carboxylate (0.28 g, 0.894mmol, 41.0% yield): LC/MS (Table 1, Method a) R_(t)=2.29 min; MS m/z 314(M+H)⁺.

Step D:4-((1-acryloylazetidin-3-yl)oxy)-1H-indole-7-carboxamide

A mixture of tert-butyl3-((7-cyano-1H-indol-4-yl)oxy)azetidine-1-carboxylate (0.28 g, 0.894mmol) and potassium carbonate (0.309 g, 2.234 mmol) in DMSO (2.98 mL)was cooled to about 10° C. by ice-cold water bath, then hydrogenperoxide (0.091 ml, 0.894 mmol) was added dropwise. The reaction mixturewas stirred at rt for about 18 h, hydrogen peroxide (0.023 mL, 0.225mmol) was added. The reaction mixture was stirred at rt for about anadditional 9 h. Water (30 mL) was added to the reaction mixture and themixture was extracted with EtOAc (2×30 mL) and the combined organiclayers were dried over sodium sulfate, filtered and concentrated toafford the crude tert-butyl3-((7-carbamoyl-1H-indol-4-yl)oxy)azetidine-1-carboxylate, which wasused directly in the next step. To a suspension of tert-butyl3-((7-carbamoyl-1H-indol-4-yl)oxy)azetidine-1-carboxylate (0.27 g, 0.815mmol) in MeOH (4.45 mL) was added hydrogen chloride (4.0 M in dioxane,4.07 mL, 16.30 mmol) dropwise, the mixture was stirred at rt for about30 min, then the mixture was concentrated in vacuo to afford the crude4-(azetidin-3-yloxy)-1H-indole-7-carboxamide hydrochloride, which wasused directly in the next step.

The suspension of 4-(azetidin-3-yloxy)-1H-indole-7-carboxamidehydrochloride (0.218 g, 0.815 mmol) in DCM (13.0 mL) was cooled to about−10° C. in an ice/sodium chloride bath, TEA (0.568 mL, 4.08 mmol) wasadded dropwise; then a solution of acryloyl chloride (0.075 mL, 0.897mmol) in DCM (3.26 mL) was added dropwise via syringe and the reactionmixture was stirred for about 30 min. The reaction mixture wasconcentrated in vacuo, the crude material was purified by silica gelchromatography eluting with a gradient of 0 to 10% MeOH/DCM to afford4-((1-acryloylazetidin-3-yl)oxy)-1H-indole-7-carboxamide (0.16 g, 0.555mmol, 68.1% yield): LC/MS (Table 1, Method a) R_(t)=1.37 min; MS m/z 286(M+H)⁺. (Btk IC₅₀=A)

Example #28*:(S)-4-(1-(1-Acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide and(R)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide

Step A: tert-butyl3-(1-(((trifluoromethyl)sulfonyl)oxy)vinyl)azetidine-1-carboxylate andtert-butyl3-(1-(((trifluoromethyl)sulfonyl)oxy)ethylidene)azetidine-1-carboxylate

To a solution of diisopropylamine (0.646 mL, 4.57 mmol) in THF (3.8 mL)at about 0° C. was added a solution of n-butyllithium (2 M in hexanes)(2.28 mL, 4.57 mmol) dropwise (internal temperature maintained belowabout 3° C.). The reaction mixture was stirred at about 0° C. for about30 min, and was cooled down to about −78° C. A solution of tert-butyl3-acetylazetidine-1-carboxylate (0.758 g, 3.81 mmol) in THF (7.6 mL) wasadded dropwise (keeping the internal temperature below about −70° C.),and reaction mixture was then stirred at about −78° C. for about 30 min.A solution of1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1.42 g, 4.00 mmol) in THF (7.6 mL) was added dropwise (keeping theinternal temperature below about −70° C.). After addition, the mixturewas allowed to warm to about 0° C. over about 4 h, and the reactionmixture was quenched with saturated NH₄Cl and extracted with EtOAc (3×50mL), concentrated and purified by silica gel chromatography eluting witha gradient of 0-15% EtOAc/heptane to afford a mixture of tert-butyl3-(1-(((trifluoromethyl)sulfonyl)oxy)vinyl)azetidine-1-carboxylate andtert-butyl3-(1-(((trifluoromethyl)sulfonyl)oxy)ethylidene)azetidine-1-carboxylateas a yellow oil (0.398 g, 31%): ¹H NMR (400 MHz, CDCl₃) tert-butyl3-(1-(((trifluoromethyl)sulfonyl)oxy)vinyl)azetidine-1-carboxylate: δ5.32 (d, J=4.2 Hz, 1H), 5.16 (dd, J=4.2, 1.0 Hz, 1H), 4.15 (t, J=8.8 Hz,2H), 3.93 (dd, J=8.8, 6.1 Hz, 2H), 3.49-3.37 (m, 1H), 1.44 (s, 9H);tert-butyl3-(1-(((trifluoromethyl)sulfonyl)oxy)ethylidene)azetidine-1-carboxylate:δ 4.58-4.53 (m, 2H), 4.52-4.49 (m, 2H), 1.98-1.94 (m, 3H), 1.45 (s, 9H)

Step B: tert-butyl3-(1-(7-carbamoyl-1H-indol-4-yl)vinyl)azetidine-1-carboxylate andtert-butyl3-(1-(7-carbamoyl-1H-indol-4-yl)ethylidene)azetidine-1-carboxylate

To a vial charged with a mixture of tert-butyl3-(1-(((trifluoromethyl)sulfonyl)oxy)vinyl)azetidine-1-carboxylate andtert-butyl3-(1-(((trifluoromethyl)sulfonyl)oxy)ethylidene)azetidine-1-carboxylate(0.388 g, 1.17 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide(0.279 g, 0.975 mmol), Pd(dppf)Cl₂(0.043 g, 0.059 mmol) and sodiumcarbonate (0.31 g, 2.93 mmol) was added 1,4-dioxane (3 mL) and water (1mL). The reaction mixture was evacuated and filled with nitrogen(repeated 3 times). The mixture was then heated at about 80° C. forabout 1 h. The reaction mixture was concentrated and diluted withMeOH/DCM. The mixture was filtered and washed with MeOH/DCM and thefiltrate was concentrated to dryness. The crude product was purified bysilica gel chromatography eluting with a gradient of 0-3% MeOH/DCM togive a mixture of tert-butyl3-(1-(7-carbamoyl-1H-indol-4-yl)vinyl)azetidine-1-carboxylate andtert-butyl3-(1-(7-carbamoyl-1H-indol-4-yl)ethylidene)azetidine-1-carboxylate(0.277 g, 83%) as a yellow oil: LC/MS (Table 1, Method a) R_(t)=2.08,2.13 min.; MS m/z: 340 (M−H)⁻.

Step C: tert-butyl3-(1-(7-carbamoyl-1H-indol-4-yl)ethyl)azetidine-1-carboxylate

To a flask charged with 10 wt % Pd/C (0.026 g, 0.024 mmol) was added asolution of tert-butyl3-(1-(7-carbamoyl-1H-indol-4-yl)vinyl)azetidine-1-carboxylate andtert-butyl3-(1-(7-carbamoyl-1H-indol-4-yl)ethylidene)azetidine-1-carboxylate (0.26g, 0.76 mmol) in EtOAc (10 mL) and about 2 drops of MeOH. The mixturewas hydrogenated with a hydrogen balloon at about rt for about 2 h. Thereaction mixture was filtered through a pad of Celite® and washed withEtOAc. The filtrate was concentrated to dryness to give tert-butyl3-(1-(7-carbamoyl-1H-indol-4-yl)ethyl)azetidine-1-carboxylate (0.212 g,81%) as a light yellow foam: LC/MS (Table 1, Method a) R_(t)=2.08 min.;MS m/z: 342 (M−H)⁻.

Step D: (S)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamideand (R)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide

tert-Butyl 3-(1-(7-carbamoyl-1H-indol-4-yl)ethyl)azetidine-1-carboxylate(0.17 g, 0.495 mmol) was purified by preparative chiral HPLC (Table 2,Method 1) to give(S)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide (0.063g, 37%) (R_(t)=12.339 min, or =positive) and(R)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide (0.066g, 39%) (R_(t)=18.959 min, or =negative).

Step E.1:(S)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide

To a vial charged with (S)-tert-butyl3-(1-(7-carbamoyl-1H-indol-4-yl)ethyl)azetidine-1-carboxylate (0.063 g,0.183 mmol) and MeOH (1 mL) was added hydrogen chloride (4 M in dioxane,0.92 mL, 3.67 mmol) at about rt. The mixture was stirred for about 30min, then the mixture was concentrated in vacuo to afford the crude(S)-tert-butyl3-(1-(7-carbamoyl-1H-indol-4-yl)ethyl)azetidine-1-carboxylatehydrochloride that was used without additional purification.

To a suspension of(S)-4-(1-(azetidin-3-yl)ethyl)-1H-indole-7-carboxamide hydrochloride(0.051, 0.183 mmol) in THF (2 mL) and DCM (1 mL) at about 0° C. wasadded N-ethyl-N-isopropylpropan-2-amine (0.096 mL, 0.550 mmol) followedby acryloyl chloride (0.017 mL, 0.202 mmol). The mixture was stirred atabout 0° C. for about 30 min. The mixture was quenched with MeOH, andthe volatiles were removed under reduced pressure. The residue waspartitioned between DCM and saturated aqueous NaHCO₃. The organic layerwas concentrated, and the crude product was purified by silica gelchromatography eluting with a gradient of 0-5% MeOH/DCM to afford(S)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide (0.039g, 69.9%) as a white solid: LC/MS (Table 1, Method a) R_(t)=1.50 min.;MS m/z: 298 (M+H)⁺. (Btk IC₅₀=B)

Step E.2:(R)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide

To a vial charged with (R)-tert-butyl3-(1-(7-carbamoyl-1H-indol-4-yl)ethyl)azetidine-1-carboxylate (0.066 g,0.192 mmol) and MeOH (1 mL) was added hydrogen chloride (4 M in dioxane,0.96 mL, 3.84 mmol) at about rt. The mixture was stirred at rt for about1 h, then the mixture was concentrated in vacuo to afford the crude(R)-tert-butyl3-(1-(7-carbamoyl-1H-indol-4-yl)ethyl)azetidine-1-carboxylatehydrochloride that was used without additional purification.

To a suspension of(R)-4-(1-(azetidin-3-yl)ethyl)-1H-indole-7-carboxamide hydrochloride(0.054 g, 0.192 mmol) in THF (2 mL) and DCM (1 mL) at about 0° C. wasadded N-ethyl-N-isopropylpropan-2-amine (0.1 mL, 0.577 mmol) followed bydropwise addition of acryloyl chloride (0.018 mL, 0.212 mmol). Themixture was stirred at about 0° C. for about 30 min. The mixture wasquenched with MeOH, and the volatiles were removed under reducepressure. The residue was partitioned between DCM and saturated aqueousNaHCO₃. The organic layer was concentrated, and the crude product waspurified by silica gel chromatography eluting with a gradient of 0-5%MeOH/DCM to afford(R)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide (0.042g, 73.2%) as a white solid. LC/MS (Table 1, Method a) R_(t)=1.50 min.;MS m/z: 298 (M+H)⁺. (Btk IC₅₀=A)

Example #29:4-((1-Acryloylazetidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-c]pyridine-7-carboxamideStep A: 4-bromo-1H-pyrrolo[2,3-c]pyridine-7-carbonitrile

To a solution of 4-bromo-1H-pyrrolo[2,3-c]pyridine [ChemTec] (10.4 g,52.8 mmol) in DCM (66.0 mL) and DME (66.0 mL) was added3-chlorobenzoperoxoic acid (21.29 g, 95 mmol, 77% by weight) in oneportion and the mixture was allowed to stir for about 16 h. The organicsolvents were removed under reduced pressure, the solid triturated withDCM and the solid filtered to yield a mixture of both product andbenzoic acid. The filtrate still contained additional product and it wasconcentrated further under reduced pressure to enable a secondfiltration. The combined filtercakes were dried and transferred to a 1 Lround bottom flask containing a magnetic stir bar. MeCN (264 mL) and TEA(14.8 mL, 106 mmol) were added to give an off-white slurry.Trimethylsilyl cyanide (24.64 mL, 185 mmol) was added in one portion viasyringe and the mixture was heated to reflux. After about 2 h of heatingthe mixture was allowed to cool to rt. The reaction was quenched by theaddition of 100 mL of 1 M NaOH, diluted with 100 mL of EtOAc,transferred to a separatory funnel and further diluted with 100 mL of 1M NaOH and 100 mL of EtOAc. The layers were separated and the aqueousphase was extracted with EtOAc (3×150 mL). The combined organic extractswere washed with at 1:1 mixture of brine and 1 M NaOH (2×50 mL), driedover Na₂SO₄, filtered and the solvent was removed to afford4-bromo-1H-pyrrolo[2,3-c]pyridine-7-carbonitrile as a brown-yellow solid(10.28 g, 80%). ¹H NMR (400 MHz, DMSO) δ 8.44 (s, 1H), 7.96 (d, J=3.1Hz, 1H), 6.71 (d, J=3.1 Hz, 1H).

Step B:4-bromo-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

To a solution of 4-bromo-1H-pyrrolo[2,3-c]pyridine-7-carbonitrile (10.2g, 45.9 mmol) in EtOH (104 mL) were added a 1 M aqueous solution of NaOH(115 mL, 115 mmol) and 30% hydrogen peroxide (80 mL, 781 mmol) and thereaction mixture was heated to about 45° C. and stirred for about 30min. The organic solvent was removed under reduced pressure. The mixturewas diluted with 30 mL of water and filtered to afford4-bromo-1H-pyrrolo[2,3-c]pyridine-7-carboxamide as a light yellow solid(9.87 g, 83%). LC/MS (Table 1, Method as): R_(t)=1.81 min; MS m/z: 240,242 (M+H)⁺.

Step C: tert-butyl3-((7-carbamoyl-1H-pyrrolo[2,3-c]pyridin-4-yl)(methyl)amino)azetidine-1-carboxylate

4-Bromo-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (580 mg, 2.416 mmol) wasdissolved in 12 mL of anhydrous dioxane and dried for about 1 h overNa₂SO₄. The solution was then filtered into an oven-dried 75 mL pressurevessel and the drying agent washed using 3 mL of dioxane. The solutionwas degassed using a stream of argon and tert-butyl3-(methylamino)azetidine-1-carboxylate hydrochloride (0.969 g, 4.35mmol, Synthonix) was added followed bychloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)(0.089 g, 0.12 mmol) and X-Phos (0.057 g, 0.12 mmol). The mixture wasdegassed for about 10 min and LiHMDS (1 M in THF, 10.87 mL, 10.87 mmol)was added dropwise via syringe, the vial sealed and heated to about 90°C. for about 19 h. The reaction was cooled to rt and quenched byaddition of aqueous NaHCO₃ (20 mL) and diluted with EtOAc (50 mL).Further dilution using water (10 mL) and brine (10 mL) led to completedissolution and the layers were separated. The aqueous phase wasextracted with EtOAc (3×20 mL). The combined organic extracts werewashed with 1:1 brine and aqueous NaHCO₃ (20 mL), dried over Na₂SO₄,filtered and the solvent was removed under reduced pressure. The crudematerial was deposited onto silica and purified using a silica column(40 g), eluting with 0-5% of MeOH/DCM. The fractions containing productwere concentrated under reduced pressure to afford tert-butyl3-((7-carbamoyl-1H-pyrrolo[2,3-c]pyridin-4-yl)(methyl)amino)azetidine-1-carboxylateas a light-yellow solid (0.61 g, 69%). ¹H NMR (400 MHz, DMSO) δ 11.41(bs, 1H), 7.90 (bs, 1H), 7.48-7.43 (m, 1H), 7.43-7.39 (m, 2H), 6.60 (dd,J=3.1, 2.0 Hz, 1H), 4.61-4.51 (m, 1H), 4.23-4.14 (m, 2H), 3.86 (dd,J=8.9, 5.2 Hz, 2H), 3.06 (s, 3H), 1.38 (s, 9H).

Step D:4-(azetidin-3-yl(methyl)amino)-1H-pyrrolo[2,3-c]pyridine-7-carboxamidehydrochloride

To a 50 mL round bottom flask containing a magnetic stir bar and MeOH(1.97 mL) was added acetyl chloride (1307 μl, 18.38 mmol) at about 0° C.via syringe. After about 10 min, the mixture was warmed to rt andstirred for about 1 h. Then, a solution of tert-butyl3-((7-carbamoyl-1H-pyrrolo[2,3-c]pyridin-4-yl)(methyl)amino)azetidine-1-carboxylate(127 mg, 0.368 mmol) in MeOH (1970 μL) and DCM (657 μL) was addeddropwise via syringe and the reaction stirred for about 5 h at rt. Thesolvents were removed under reduced pressure to afford4-(azetidin-3-yl(methyl)amino)-1H-pyrrolo[2,3-c]pyridine-7-carboxamidehydrochloride (128 mg, 99%).LC/MS (Table 1, Method at): R_(t)=0.93 min.;MS m/z: 246 (M+H)⁺.

StepE:4-((1-acryloylazetidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide

To a cooled solution of the4-(azetidin-3-yl(methyl)amino)-1H-pyrrolo[2,3-c]pyridine-7-carboxamidehydrochloride (101 mg, 0.36 mL) in DCM (5760 μL) andethyldiisopropylamine (258 μL, 1.440 mmol) was added a solution ofacryloyl chloride (50 mg, 0.552 mmol) in DCM (1440 μL) dropwise viasyringe keeping the internal temperature at or below at −4° C. Themixture was allowed to stir for 15 min. The reaction was quenched byaddition of 0.3 mL of water, the solvent volume reduced to 1.5 mL andthe mixture loaded onto 4 g of silica. The material was purified using a24 g silica column, 0-10% MeOH/DCM. The fractions containing productwere concentrated under reduced pressure to afford4-((I-acryloylazetidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-c]pyridine-7-carboxamideas a white solid (89 mg, 78%). ¹H NMR (400 MHz, DMSO) δ 11.43 (bs, 1H),7.98-7.88 (m, 1H), 7.49-7.44 (m, 2H), 7.42 (s, 1H), 6.64-6.58 (m, 1H),6.40-6.29 (m, 1H), 6.11 (dd, J=17.0, 2.2 Hz, 1H), 5.68 (dd, J=10.2, 2.2Hz, 1H), 4.72-4.62 (m, 1H), 4.60-4.52 (m, 1H), 4.31-4.18 (m, 2H), 3.97(dd, J=10.5, 5.2 Hz, 1H), 3.08 (s, 3H); MS m/z: 300 (M+H)⁺. (Btk IC₅₀=A)

Example #30*: (R)-4-(1-Acryloylpiperidin-3-yl)-1H-indole-7-carboxamideand (S)-4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide

A sample of 4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide (0.03g, 0.10 mmol) was purified via preparative chiral HPLC (Table 2, Method2) to give (R)-4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide(0.012 g, 40%)(R_(t)=17.14 min, or =positive) (Btk IC₅₀=B) and(S)-4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide (0.013 g,43%)(R_(t)=20.46 min, or =negative) (Btk IC₅₀=A): LC/MS (Table 1, Methoda) R_(t)=1.47 min.; MS mz: 298 (M+H)⁺.

TABLE 3 Examples prepared from an acryloyl amide using chiral method:Table 2, Method 4 R_(t) min m/z (Table 1, ESI+ Btk Acryloyl AmideProduct Example # Method) (M + H)⁺ IC₅₀ 4-(Azetidin-3-yl)(methyl)amino)-2- (tetrahydrofuran-3-yl)-1H- indole-7-carboxamide(Example #E.9.21)

5.1 1.37 (ax) 369 A 4-(Azetidin-3- yl)(methyl)amino)-2-(tetrahydrofuran-3-yl)-1H- indole-7-carboxamide (Example #E.9.21)

5.2 1.37 (ax) 369 A

TABLE 4 Examples prepared from an acryloyl amide using chiral method:Table 2, Method 15 R_(t) min m/z (Table 1, ESI+ Btk Acryloyl AmideProduct Example # Method) (M + H)⁺ IC₅₀ 4-(1,4-Oxazepan-6-yl)-1H-pyrrolo[2,3-c]pyridine-7- carboxamide (Prepared using L with Preparation#49 and Pd(OH)₂, G with HCl and E with acryloyl chloride)

3.1 1.27 (as) 315 B 4-(1,4-Oxazepan-6-yl)-1H- pyrrolo[2,3-c]pyridine-7-carboxamide (Prepared using L with Preparation #49 and Pd(OH)₂, G withHCl and E with acryloyl chloride)

3.2 1.26 (as) 315 B

TABLE 5 Examples prepared from an acryloyl amide using chiral method:Table 2, Method 16 R_(t) min m/z (Table 1, ESI+ Btk Acryloyl AmideProduct Example # Method) (M + H)⁺ IC₅₀ 2-(1-Methyl-1H-pyrazol-4-yl)-4-(piperidin-3-yl)-1H- indole-7-carboxamide hydrochloride (Preparedusing A from Preparation #10 with tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,4- dihydropyridine-1(2H)-carboxylate [Anisyn], L with Pd/C, G with acetyl chloride, E withacryloyl chloride)

4.1 1.54 (ba) 378 A 2-(1-Methyl-1H-pyrazol-4- yl)-4-(piperidin-3-yl)-1H-indole-7-carboxamide hydrochloride (Prepared using A from Preparation#10 with tert-butyl 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydropyridine-1(2H)- carboxylate [Anisyn], Lwith Pd/C, G with acetyl chloride, E with acryloyl chloride)

4.2 1.58 (ba) 378 A

What is claimed:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt, pro-drug, biologically activemetabolite, isomer, or stereoisomer thereof, wherein: X is NR² or S; Yis N or CR¹, and Z is N or CR¹; or, Y is CR¹R² and Z is CR¹R²; A is N orCR⁴; E is N or CR⁵; R′ is independently H, deuterium, CN, halogen, CF₃,—NR^(c)R^(c), —N(R^(a))C(O)R^(b), optionally substituted (C₁-C₆)alkyl,optionally substituted (C₂-C₆)alkenyl, optionally substituted aryl,optionally substituted (C₃-C₆)cycloalkyl, optionally substituted(C₃-C₆)cycloalkenyl, optionally substituted heteroaryl, or optionallysubstituted saturated or partially saturated heterocyclyl; R² isindependently H, deuterium, or optionally substituted (C₁-C₃)alkyl; R³is halogen, —N(R^(a))₂, optionally substituted aryl, optionallysubstituted (C₃-C₇)cycloalkyl, optionally substituted saturated orpartially saturated heterocyclyl, or optionally substituted heteroaryl;or R³ is —R³⁰¹-L-R³⁰² wherein R³⁰¹ is a bond, —O—, —OCH₂—, —NR^(d)—, oroptionally substituted (C₁-C₃)alkylene, and L is optionally substitutedphenyl, optionally substituted (C₃-C₆)cycloalkyl, optionally substitutedheteroaryl or a saturated or partially saturated heterocyclyl containingone or more heteroatoms, at least one of which is nitrogen; or L is-L¹-L² wherein L¹ is attached to R³⁰¹ and L¹ is optionally substitutedphenyl, optionally substituted heteroaryl or optionally substitutedsaturated or partially saturated carbocycle or a saturated or partiallysaturated heterocyclyl; and L² is a bond, CH₂, NR^(d), CH₂N(H),S(O)₂N(H), or —O—; R³⁰² is CN, —CH₂CN, optionally substituted—C(═O)R^(302a), (CH₂)_(n)-optionally substituted saturated or partlysaturated heterocyclyl or optionally substituted —S(O)₂(C₂)alkenyl;wherein R^(302a) is optionally substituted (C₁-C₄)alkyl, optionallysubstituted (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, —C(O)—(C₁-C₄)alkyl,optionally substituted saturated or partially unsaturated(C₃-C₆)cycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, —N(H)— optionally substituted heteroaryl or —(CH₂)_(n)optionally substituted unsaturated or partly saturated heterocyclyl; R⁴is H, deuterium, CN, optionally substituted (C₁-C₃)alkyl, optionallysubstituted (C₃-C₆) cycloalkyl or optionally substituted saturated orpartially saturated heterocyclyl, or optionally substituted heteroaryl;wherein the optionally substituted saturated or partially saturatedheterocyclyl; and optionally substituted heteroaryl contain at least onenitrogen atom; or R³ and R⁴, together with the carbon atoms to whichthey are attached, form an optionally substituted, saturated,unsaturated or partially unsaturated 5 or 6 membered carbocyclic ring oran optionally substituted, saturated, or partially unsaturated 5 or 6membered heterocyclic ring containing one or more heteroatoms selectedfrom N, S and O; R⁵ is H, deuterium, halogen, or optionally substituted(C₁-C₃)alkyl; R^(a) is independently selected from H, —C(O)-optionallysubstituted (C₂-C₆)alkenyl, optionally substituted (C₁-C₆)alkyl,—(CH₂)_(n)-optionally substituted (C₃-C₆)cycloalkyl,—(CH₂)_(n)-optionally substituted heterocyclyl, or —(CH₂)_(n)-optionallysubstituted heteroaryl; R^(b) is H, optionally substituted (C₁-C₆)alkyl,optionally substituted (C₂-C₆)alkenyl, optionally substituted(C₂-C₆)alkynyl, —CH₂—O-optionally substituted aryl, or —CH₂—O-optionallysubstituted heteroaryl; R^(c) is independently H, optionally substituted(C₁-C₆)alkyl, optionally substituted (C₃-C₆)cycloalkyl, optionallysubstituted saturated or partially saturated heterocyclyl, optionallysubstituted aryl or optionally substituted heteroaryl; R^(d) is H,optionally substituted heterocyclyl, —(CH₂)-optionally substituted(C₃-C₆)cycloalkyl, —(CH₂)-optionally substituted heteroaryl oroptionally substituted (C₁-C₃)alkyl; R^(f) is optionally substituted(C₁-C₃)alkyl, optionally substituted (C₂-C₄)alkenyl or optionallysubstituted (C₂-C₄)alkynyl; and n is independently 0 or
 1. 2. Thecompound according to claim 1, wherein Y is CR′ and R′ of Y is H,optionally substituted ethenyl, optionally substituted ethyl, optionallysubstituted methyl, optionally substituted 2,3-dihydrobenzofuranyl,optionally substituted 1,4-dioxanyl, optionally substituted3,4-dihydro-2H-benzo[b][1,4]oxazinyl, optionally substituted6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, optionally substitutedchromanyl, optionally substituted cyclohexenyl, optionally substitutedcyclopropyl, optionally substituted tetrahydrofuranyl, optionallysubstituted isochromanyl, optionally substituted1,2,3,4-tetrahydro-isoquinolinyl, optionally substituted isoxazolyl,optionally substituted morpholinyl, optionally substituted oxetanyl,optionally substituted phenyl, optionally substituted piperidinyl,optionally substituted piperazinyl, optionally substituted3,6-dihydro-2H-pyranyl, optionally substituted pyrano[4,3-b]pyridinyl,optionally substituted pyrazolyl, optionally substituted pyridinyl,optionally substituted 3H-pyridin-1-one, optionally substituted1,2,3,6-tetrahydropyridinyl, optionally substituted pyrimidinyl,optionally substituted pyrrolidinyl, optionally substituted2,5-dihydropyrrolyl, optionally substituted tetrahydropyranyl oroptionally substituted tetrahydro-2H-thiopyranyl.
 3. The compoundaccording to claim 2 wherein R′ is H or R′ is optionally substituted byone or more substituents independently selected from the groupconsisting of CN, OH, ═O, halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,—CH₂CH₂OH, —CH₂C(CH₃)₂₀H,—CH₂CH(OH)CH₂OH, —CH═CH₂, —CH₂NH₂,—CH₂N(H)C(O)R^(e), —C(O)(C₁-C₄)alkyl, —C(O)(C₁-C₄)alkoxy, —C(O)NH₂,—C(O)N(CH₃)₂,—C(O)-optionally substituted heterocyclyl, —N(H)C(O)CH₃,N(CH₃)₂, —S(O)₂(C₁-C₄)alkyl, —S(O)₂-pyrrolidinyl, (C₁-C₄)alkoxy,—CH₂-morpholinyl, —CH₂CH₂-morpholinyl, morpholinyl, tetrahydropyranyl;wherein R^(e) is (C₁-C₃)alkyl, —CH₂Cl, —C≡CH, —C≡CCH₃, —CH═CH₂,—CH═CHCH₃, —C(═CH₂)CH₃, —CH₂CN, —CH₂CH₂N(CH₃)₂, —CH₂CH₂-piperidinyl,—CH₂O-optionally substituted phenyl.
 4. The compound according to claim3, wherein R³ is —N(H)C(O)CH═CH₂, optionally substituted isoxazolyl,optionally substituted phenyl, optionally substituted pyrazolyl,optionally substituted pyridinyl, optionally substituted pyrimidinyl,optionally substituted thiazolyl, or optionally substituted thienyl. 5.The compound according to claim 4, wherein R³ is optionally substitutedby one or more substituents independently selected from —NH₂, —NHCH₃,(C₁-C₄)alkyl and —C(O)(C₂-C₄)alkenyl.
 6. The compound according to claim5, wherein X is NR² and R² is H.
 7. The compound according to claim 6,wherein Y is CR′ and R′ of Y is H, optionally substituted phenyl,optionally substituted piperazinyl, optionally substituted pyrazolyl, oroptionally substituted 1,2,3,6-tetrahydropyridinyl.
 8. The compoundaccording to claim 7, wherein Y is CR′ and R′ of Y is optionallysubstituted by one or more substituents independently selected fromhalogen, (C₁-C₄)alkyl, —C(O)(C₁-C₄)alkyl, and —S(O)₂(C₁-C₄)alkyl.
 9. Thecompound according to claim 8, wherein Z is N or Z is CR′ and R′ of Z isH; and A is CR⁴ and R⁴ is H or azetidinyl substituted with —C(O)CH═CH₂.10. The compound according to claim 9, wherein the compound is4-(3-amino-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;2-(4-fluorophenyl)-4-(pyridin-3-yl)-1H-indole-7-carboxamide;4-(pyridin-3-yl)-2-p-tolyl-1H-indole-7-carboxamide;2-(4-fluorophenyl)-4-(pyridin-4-yl)-1H-indole-7-carboxamide;2-(4-fluorophenyl)-4-(1H-pyrazol-5-yl)-1H-indole-7-carboxamide;4-(3,5-dimethylisoxazol-4-yl)-2-p-tolyl-1H-indole-7-carboxamide;2-(1-acetylpiperidin-4-yl)-4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide;4-(pyridin-4-yl)-2-p-tolyl-1H-indole-7-carboxamide;4-(thiophen-2-yl)-2-p-tolyl-1H-indole-7-carboxamide;4-(2-aminophenyl)-1H-indole-7-carboxamide;4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide;4-(5-aminopyridin-3-yl)-1H-indole-7-carboxamide;4-(2-aminopyridin-4-yl)-1H-indole-7-carboxamide;4-(2-aminoethylamino)-2-(4-fluorophenyl)-1H-indole-7-carboxamide;4-(2-aminoethylamino)-2-p-tolyl-1H-indole-7-carboxamide;4-(pyrimidin-5-yl)-2-p-tolyl-1H-indole-7-carboxamide;4-(1H-pyrazol-4-yl)-2-p-tolyl-1H-indole-7-carboxamide;4-(1H-pyrazol-5-yl)-2-p-tolyl-1H-indole-7-carboxamide;2-(4-fluorophenyl)-4-(pyrimidin-5-yl)-1H-indole-7-carboxamide;4-(thiazol-2-yl)-2-p-tolyl-1H-indole-7-carboxamide;4-(pyridin-2-yl)-2-p-tolyl-1H-indole-7-carboxamid;4-(thiophen-3-yl)-2-p-tolyl-1H-indole-7-carboxamide;4-(1-methyl-1H-pyrazol-4-yl)-2-p-tolyl-1H-indole-7-carboxamide;4-(1H-pyrazol-3-yl)-2-p-tolyl-1H-indole-7-carboxamide;4-(2-aminophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-phenyl-1H-indole-7-carboxamide;4-(3-amino-2-methylphenyl)-2-(4,4-difluorocyclohex-1-enyl)1H-indole-7-carboxamide;4-(3-amino-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide;4-(1-acryloylpiperidin3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;4-(2-aminoethylamino)-2-p-tolyl-1H-indole-7-carboxamide;4-((1R,2R)-2-aminocyclohexylamino)-2-(4-fluorophenyl)-1H-indole-7-carboxamide*;4-(1-methyl-1H-pyrazol-5-ylamino)-2-p-tolyl-1H-indole-7-carboxamide;4-iodo-2-(pyridin-3-yl)-1H-indole-7-carboxamide;4-(3-amino-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3,5-dimethylisoxazol-4-yl)-2-(4-fluorophenyl)-1H-indole-7-carboxamide;4-(2-aminophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;or2-(1-Acetylpiperidin-4-yl)-4-(3-amino-2-methylphenyl)-1H-indole-7-carboxamide.11. The compound according to claim 3, wherein R is —R³⁰¹-L-R³⁰², andR³⁰¹ is a bond, N(H), N(CH₃), CH₂, C(H)(optionally substituted(C₁-C₃)alkyl), O, or OCH₂.
 12. The compound according to claim 11wherein L is optionally substituted azetidinyl, optionally substitutedcyclopentyl, optionally substituted 3,6-diazabicyclo[3.2.0]heptanyl,optionally substituted 1,4-dioxanyl, optionally substituted morpholinyl,optionally substituted [1,4]oxepanyl, optionally substituted phenyl,optionally substituted piperidinyl, or optionally substitutedpyrrolidinyl; or L is L¹-L² wherein L¹ is optionally substitutedcyclohexyl, optionally substituted cyclopentyl optionally substitutedphenyl, optionally substituted piperidinyl, optionally substitutedpyridinyl; L² is N(H), N(CH₃), N(CH₂CH₂OH), N(CH₂CH(CH₃)₂), N(oxetanyl),N(CH₂-cyclopentyl), N(CH₂-thiazolyl), O, S(O)₂N(H), or CH₂N(H).
 13. Thecompound according to claim 12, wherein L or L¹ is optionallysubstituted with one or more substituents independently selected fromhalogen, CN, OH, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, —CH₂OH,—N(H)CH₂-heteroaryl, benzyloxy, and —OCH₂-heteroaryl.
 14. The compoundaccording to claim 13, wherein R³⁰² is —C(O)CH₃, —C(O)C(O)CH₃,—C(O)CF₂(Cl), —CH(CH₃)₂, —CH₂Cl, —CH₂CN, —C(O)CH₂CN, —C(O)CH₂CH₃,—C(O)CH₂F, —C(O)CH(CH₃)₂, —C(O)—CH₂CH(CH₃)₂, —C(O)CH(CH₃)(Cl),—C(O)CH₂CH(CH₃)CH₃, —C(O)CH(Cl)CH₂CH₃, —CH₂CH₂OH, —C(O)CH₂CH₂N(CH₃)₂,—C(O)CH═CH₂, —C(O)C≡CH, —C(O)CH═CHCl, —C(O)CH═CHCH₃, —C(O)C(═CH₂)CH₃,—C(O)C(CH₂CH₃)═CH₂, —C(O)CH═CHCH(CH₃)₂, —C(O)CH═CHC(O)OH,—C(O)CH═CHC(O)N(H)CH₂CH₃, —C(O)CH═CHCH₂N(CH₃)₂, —C(O)CH═CHC(O)OCH₃,—C(O)CH═CHC(O)OCH₂CH₃, —C(O)CH═CHC(O)N(H)CH₃, —C(O)CH═CHC(O)CH₂CH₂OCH₃,—C(O)CH═CHC(O)N(CH₃)₂, —C(O)CH═CHC(O)N(H)CH₂CH₃,—C(O)CH═CHC(O)N(H)CH₂CH₂OCH₃, —C(O)CH═CHCH₂N(H)CH₂CH₂OCH₃,—C(O)C(CN)═C(OH)(CH₃), —C(O)CH═CH-optionally substitutedpyrazolyl-C(O)CH═CHCH₂N(H)-optionally substituted cyclopropyl,—C(O)CH═CHCH₂N(H)CH₂-optionally substituted tetrahydrofuranyl,—C(O)CH═CHC(O)NH₂,—C(O)CH═CHC(O)N(H)— optionally substitutedcyclopropyl, —C(O)C(CH₃)═CHCH₃, —C(O)C(CH₃)═CHCH₂CH₃,—C(O)C(═CH₂)CH₂N(CH₃)₂, —C(O)C(═CH₂)CH₂NH₂, —C(O)C(═CH₂)CH₂N(H)(CH₃),—C(O)C(═CH₂)CH₃, —C(O)C(═CH₂)CH₂— optionally substituted morpholinyl,—C(O)C(═CH₂)-optionally substituted phenyl, —CH₂— optionally substitutedbenzo[d]isothiazolyl, —C(O)—CH₂—O-optionally substituted phenyl,—CH₂-optionally substituted thiazolyl, —CH₂CH₂-optionally substitutedmorpholinyl, —C(O)CH₂O-optionally substituted phenyl,—C(O)CH₂CH₂-optionally substituted piperazinyl, —C(O)CH₂CH₂— optionallysubstituted piperidinyl, —C(O)CH₂O-optionally substituted pyridinyl,—C(O)CH₂CH₂ optionally substituted pyrrolidinyl,—C(O)CH═CH optionallysubstituted cyclopropyl,—C(O)CH═CHCH₂— optionally substitutedmorpholinyl, —C(O)CH═CHCH₂— optionally substituted piperidinyl,—C(O)CH═CH— optionally substitutedpyrazolyl,—C(O)CH═CH-optionally substituted pyridinyl,—C(O)CH═CH-optionally substituted thiazolyl, —C(O)-optionallysubstituted cyclohexenyl, —C(═O)-optionally substituted cyclohexyl,—C(O)-optionally substituted cyclopentenyl, —C(O)-cyclopentyl,optionally substituted imidazo[1,2-a]pyrazinyl, optionally substitutedtetrahydroimidazo[1,2-a]pyrazinyl, optionally substituteddihydr-isoindolyl, optionally substituted1,2,3,4-tetrahydro-isoquinolinyl, optionally substituted isoquinolinyl,—C(O)-optionally substituted isoxazolyl, —C(O)-optionally substitutedoxazolyl, optionally substituted oxetanyl,—C(═O)-optionally substitutedphenyl, optionally substituted piperidinyl, —C(O)-optionally substitutedpiperidinyl, optionally substituted pyrazolyl, —C(O)CH₂O-optionallysubstituted pyridazinyl, —C(O)-optionally substituted pyridinyl,optionally substituted pyrimidinyl, optionally substituted quinazolinyl,optionally substituted dihydroquinolinyl, optionally substituted—C(O)-tetrahydrobenzo[b]thiophenyl, —C(O)-optionally substitutedtetrahydropyranyl, —C(O)-optionally substituted tetrahydropyridinyl,—C(O)-thiazolyl, —C(O)N(H)-thiazolyl, —C(O)NHCH₂CN, or —S(O)₂CH═CH₂. 15.The compound according to claim 14, wherein X is NR² and R² is H. 16.The compound according to claim 15, wherein Y is CR′ and R′ of Y isoptionally substituted with one or more substituents independentlyselected from halogen, CN, ═O, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, —CH₂NH₂,—CH₂CH₂OH, —CH₂CH(OH)CH₂CH₃, —CH₂CH(OH)CH₂OH, —CH₂CH₂OCH₂CH₃,—CH₂C(OH)(CH₃)₂, —CH₂NHC(O)(C₁-C₄)alkyl, —CH₂NHC(O)CH₂Cl,—CH₂NHC(O)CH₂CN, —CH₂NHC(O)CH₂CH₂N(CH₃)₂, —CH₂NHC(O)C(═CH₂)CH₃,—CH₂NHC(O)(C₂-C₄)alkynyl, —CH₂NHC(O)CH₂CH₂-piperidinyl,—(C₁-C₄)alkyl-morpholinyl, —CH₂NHC(O)CH₂O-phenyl wherein the phenyl isoptionally substituted with halogen, (C₁-C₄)alkoxy, —C(O)(C₁-C₄)alkyl,—C(O)(C₁-C₄)alkoxy, —C(O)N(H)₂, —C(O)N(CH₃)₂, —C(O)— morpholinyl,—C(O)-pyrrolidinyl, —N(CH₃)₂, —NHC(O)(C₁-C₄)alkyl,—NHC(O)(C₂-C₄)alkenyl, —NHC(O)CH₂CN, —S(O)₂(C₁-C₄)alkyl,—S(O)₂-pyrrolidinyl, morpholinyl, tetrahydropyranyl, or4-methylpiperazinecarbonyl.
 17. The compound according to claim 16,wherein Z is CR′ and R of Z is H, (C₁-C₄)alkyl, —NHC(O)CH₂Cl,—NHC(O)CH₂CN, —NHC(O)(C₂-C₄)alkenyl, —NHC(O)(C₂-C₄)alkynyl,—NHC(O)C(═CH₂)CH₃, —NHC(O)CH₂-phenyl wherein the phenyl is optionallysubstituted with halogen, or pyrazolyl substituted with CH₃.
 18. Thecompound according to claim 17, wherein R³⁰² is optionally substitutedwith one or more substituents independently selected from halogen, CF₃,OCF₃, ═O, CHF₂, CN, C(O)OH, OH, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₃-C₆)cycloalkyl, —(C₁-C₄)alkylCN, —(C₁-C₄)alkyC(O)NH₂, —C(O)NH₂,—C(O)N(H)(C₁-C₄)alkyl, —C(O)N(C₁-C₄)alkyl)₂, —C(O)N(H)cyclopropyl,—C(O)(C₁-C₄)alkoxy, NH₂, N(H)CH₃, N(CH₃)₂, or optionally substitutedbenzyl.
 19. The compound according to claim 1, wherein X is NR² whereinR² is H; Y is CR wherein R′ is H, CH₃, substituted pyrazolyl,6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl or tetrahydrofuranyl; Z isCR′ wherein R′ is H; E is CR⁵ wherein R⁵ is H; R³ is —R³⁰¹-L-R³⁰²wherein R³⁰¹ is a bond, —O—, —N(H)—, —N(CH₃)— or —C(H)(CH₃)—; L isazetidinyl, 3,6-diazabicyclo[3.2.0]heptanyl, morpholinyl, [1,4]oxepanyl,piperidinyl, or pyrrolidinyl; wherein the azetidinyl is optionallysubstituted with CH₃; and wherein the piperidinyl is optionallysubstituted with —CH₂OH; and R³⁰² is —C(O)CH═CH₂ or —C(O)C≡CH.
 20. Thecompound according to claim 1, wherein the compound is:4-((1-acryloylazetidin-3-yl)(methyl)amino)-1H-indole-7-carboxamide;4-(5-acetylthiophen-2-yl)-2-p-tolyl-1H-indole-7-carboxamide;4-(1-(4-methoxybenzyl)-1H-pyrazol-5-ylamino)-2-p-tolyl-1H-indole-7-carboxamide;4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)phenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;4-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;4-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-2-(4-fluorophenyl)-1H-indole-7-carboxamide;2-(4-fluorophenyl)-4-(2-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)phenyl)-1H-indole-7-carboxamide;N-(3-(7-carbamoyl-2-(pyridin-3-yl)-1H-indol-4-yl)-4-methylphenyl)thiazole-2-carboxamide2,2,2-trifluoroacetate;N-(3-(7-carbamoyl-2-(pyridin-3-yl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;(R)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide*;(R)-2-(4-fluorophenyl)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide*;(R)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide*;(R)-2-(1-methyl-1H-pyrazol-4-yl)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide*;(R)-4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-2-(4-fluorophenyl)-1H-indole-7-carboxamide*;2-(1-methyl-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;(R)-4-(3-(4-tert-butylbenzamido)piperidin-1-yl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide*;(R)-4-(3-(4-tert-butylbenzamido)piperidin-1-yl)-1H-indole-7-carboxamide*;(R)—N-(1-(7-carbamoyl-1H-indol-4-yl)piperidin-3-yl)-2-methyloxazole-4-carboxamide*;(R)-4-(3-(3-thiazol-2-ylureido)piperidin-1-yl)-1H-indole-7-carboxamide*;4-(3-(4-tert-butylbenzamido)-2-methylphenyl)-1H-indole-7-carboxamide;4-(3-(7-cyclopropyl-5-fluoro-4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide;(R)-4-(3-(4-tert-butylbenzamido)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide*;(R)-4-(3-(4-methoxybenzamido)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide*;(R)-5-tert-butyl-N-(1-(7-carbamoyl-1H-indol-4-yl)piperidin-3-yl)isoxazole-3-carboxamide*;(R)-2-(1-methyl-1H-pyrazol-4-yl)-4-(3-(4-(trifluoromethyl)benzamido)piperidin-1-yl)-1H-indole-7-carboxamide*;(R)-4-(3-(4-methoxybenzamido)piperidin-1-yl)-1H-indole-7-carboxamide*;(R)-4-(3-(4-(trifluoromethyl)benzamido)piperidin-1-yl)-1H-indole-7-carboxamide*;(R)-4-(3-(4-(difluoromethyl)benzamido)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide*;4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;2-(3,6-dihydro-2H-pyran-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;2-(4-fluorophenyl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;(R)-4-(3-(4-(1-amino-2-methyl-1-oxopropan-2-yl)benzamido)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide*;(R)-2-(1-methyl-1H-pyrazol-4-yl)-4-(3-(4-(trifluoromethoxy)benzamido)piperidin-1-yl)-1H-indole-7-carboxamide*;2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;(R)-4-(3-(6-fluoro-1-oxoisoindolin-2-yl)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide*;2-(3,6-dihydro-2H-pyran-4-yl)-4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide;2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-1H-indole-7-carboxamide;N-(3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-(hydroxymethyl)phenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;2-(1-methyl-1H-pyrazol-4-yl)-4-(2-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)phenyl)-1H-indole-7-carboxamide;(R)-4-(3-(4-cyclopropylbenzamido)piperidin-1-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide*;2-(2,5-dihydro-1H-pyrrol-3-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;2-(1-((R)-2,3-dihydroxypropyl)-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide*;N-(3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)-2-(hydroxymethyl)phenyl)thiazole-2-carboxamide;2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(4-tert-butylbenzamido)-2-methylphenyl)-1H-indole-7-carboxamide;N-(3-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-methyl-3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)phenyl)-1H-indole-7-carboxamide;2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(4-cyclopropylbenzamido)-2-methylphenyl)-1H-indole-7-carboxamide;4-(2-methyl-3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;2-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;2-(1-acetyl-2,5-dihydro-1H-pyrrol-3-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;ethyl3-(7-carbamoyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate;2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;N-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;2-(1-((S)-2,3-dihydroxypropyl)-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indole-7-carboxamide;N-(3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)-2-methylphenyl)-N-methylthiazole-2-carboxamide;N-(3-(7-carbamoyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)-2-methylphenyl)-N-(oxetan-3-yl)thiazole-2-carboxamide;2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(4-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-1H-indole-7-carboxamide;4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2-(pyrimidin-5-yl)-1H-indole-7-carboxamide;4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-2-(pyrimidin-5-yl)-1H-indole-7-carboxamide;4-(3-(4-(difluoromethyl)benzamido)-2-methylphenyl)-2-(pyrimidin-5-yl)-1H-indole-7-carboxamide;4-(3-(4-cyclopropylbenzamido)-2-methylphenyl)-2-(pyrimidin-5-yl)-1H-indole-7-carboxamide;4-(3-(6-fluoro-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;(R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(8-oxo-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide*;(R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(8-oxoimidazo[1,2-a]pyrazin-7(8H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide*;4-(2-methyl-3-(oxetan-3-ylamino)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(4-(difluoromethyl)benzamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(4-hydroxy-4-(trifluoromethyl)cyclohexanecarboxamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;(R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)-1H-indole-7-carboxamide*;2-(1-acetylpiperidin-4-yl)-4-(3-(4-cyclopropylbenzamido)-2-methylphenyl)-1H-indole-7-carboxamide;(R)—N-(1-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)piperidin-3-yl)-2-methyloxazole-4-carboxamide*;(R)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(2-oxo-1,3′-bipiperidin-1′-yl)-1H-indole-7-carboxamide*;2-(1-methyl-1H-pyrazol-4-yl)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-benzo[d]imidazole-7-carboxamide;4-(3-(4-(difluoromethyl)-N-(oxetan-3-yl)benzamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(oxetan-3-ylamino)phenyl)-1H-indole-7-carboxamide;4-(3-(4-(difluoromethyl)benzamido)-2-methylphenyl)-1H-indole-7-carboxamide;4-(3-(2-hydroxyethylamino)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;(R)—N-(1-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)piperidin-3-yl)thiazole-2-carboxamide*;4-(3-(cyclohexanecarboxamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(4-(difluoromethyl)-N-(2-hydroxyethyl)benzamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;N-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl)isothiazole-4-carboxamide;4-(2-methyl-3-(tetrahydro-2H-pyran-4-carboxamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(1-methylpiperidine-3-carboxamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(1-methylpiperidine-4-carboxamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(cyclopentanecarboxamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;N-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl)-2-methylthiazole-4-carboxamide;4-(3-(3-methoxycyclohexanecarboxamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(3-methylbutanamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-isobutyramido-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(nicotinamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;N-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl)-5-methylthiazole-2-carboxamide;N-(3-(7-carbamoyl-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-((3R,4R)-1-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-4-hydroxypiperidin-3-yl)thiazole-2-carboxamide;(R)-4-(3-acrylamidopiperidin-1-yl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide*;4-(2-methyl-3-(thiazol-2-ylmethylamino)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(N-(thiazol-2-ylmethyl)acrylamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;(Z)-4-(2-methyl-3-(2-methylbut-2-enamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;(E)-4-(3-(4-(dimethylamino)but-2-enamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(3-(piperidin-1-yl)propanamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(2-cyanoacetamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-propionamidophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-methacrylamido-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamidel;4-(3-(2-chloro-2,2-difluoroacetamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(2-chloropropanamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;(E)-4-(3-but-2-enamido-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;N1-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl);4-(3-(2-(4-fluorophenoxy)acetamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(3-(pyrrolidin-1-yl)propanamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(2-(4-cyanophenoxy)acetamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(2-(pyridin-3-yloxy)acetamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(cyclopent-1-enecarboxamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;(E)-4-(2-methyl-3-(2-methylpent-2-enamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;(Z)-4-(3-(3-chloroacrylamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;(E)-methyl4-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenylamino)-4-oxobut-2-enoate;4-(3-(cyclohex-1-enecarboxamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;(E)-ethyl4-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenylamino)-4-oxobut-2-enoate;4-(2-methyl-3-(2-phenoxyacetamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(2-fluoroacetamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(4,4-difluorocyclohex-1-enyl)-1H-indole-7-carboxamide;4-(2-(acrylamidomethyl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(3-(dimethylamino)propanamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-acrylamidophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(acrylamidomethyl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(acrylamidomethyl)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(2-cyanopyrimidin-4-ylamino)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(6-cyclopropyl-8-fluoro-1-oxoisoquinolin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;4-(3-acrylamidophenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(2-methoxypyridin-3-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(2-(pyridin-2-yloxy)acetamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;N1-(3-(7-carbamoyl-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-4-yl)-2-methylphenyl)fumaramide;4-(3-(2-chlorobutanamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(3-(4-methylpiperazin-1-yl)propanamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(2-(pyridazin-3-yloxy)acetamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(3-(thiazol-2-ylmethoxy)phenyl)-1H-indole-7-carboxamide;methyl3-(4-(3-acrylamido-2-methylphenyl)-7-carbamoyl-1H-indol-2-yl)benzoate;4-(3-acrylamido-2-methylphenyl)-2-(3-methoxyphenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(4-methoxyphenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(6-methylpyridin-3-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(3-carbamoylphenyl)-1H-indole-7-carboxamide;N-(3-(7-carbamoyl-3-methyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(3,5-dimethylisoxazol-4-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(3,5-dimethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(1-isopropyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(1-ethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(1-isobutyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;(E)-N-(3-(3-but-2-enamido-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(7-carbamoyl-3-methacrylamido-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(3-but-2-ynamido-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(7-carbamoyl-3-(2-(4-fluorophenoxy)acetamido)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(2-fluoropyridin-3-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(1-ethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;2-(3-acetamidophenyl)-4-(3-acrylamido-2-methylphenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(2-methoxypyridin-4-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(3-cyanophenyl)-1H-indole-7-carboxamide;methyl4-(4-(3-acrylamido-2-methylphenyl)-7-carbamoyl-1H-indol-2-yl)benzoate;4-(3-acrylamido-2-methylphenyl)-2-(2,3-dihydrobenzofuran-5-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(3-fluorophenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(3-(dimethylamino)phenyl)-1H-indole-7-carboxamide;4-(2-(2-chloroacetamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-acetamidophenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(2-methyl-5-(pyrrolidin-1-ylsulfonyl)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(2-fluorophenyl)-1H-indole-7-carboxamide;N-(3-(3-acrylamido-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(7-carbamoyl-3-(2-chloroacetamido)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(1-methyl-1H-pyrazol-5-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(pyridin-4-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(6-morpholinopyridin-3-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(3-(4-methylpiperazine-1-carbonyl)phenyl)-1H-indole-7-carboxamide;N-(3-(2-(2-(acrylamidomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(2-(2-(acetamidomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(7-carbamoyl-2-(2-(propionamidomethyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(2-(2-(butyramidomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;(E)-N-(3-(2-(2-(but-2-enamidomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(7-carbamoyl-2-(2-(methacrylamidomethyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(7-carbamoyl-2-(2-(propiolamidomethyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(2-(2-(but-2-ynamidomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(7-carbamoyl-2-(2-((2-cyanoacetamido)methyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(7-carbamoyl-2-(2-((3-(dimethylamino)propanamido)methyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(7-carbamoyl-2-(2-((3-(piperidin-1-yl)propanamido)methyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(7-carbamoyl-2-(2-((2-phenoxyacetamido)methyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(7-carbamoyl-2-(2-((2-(4-fluorophenoxy)acetamido)methyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(7-carbamoyl-2-(2-((2-chloroacetamido)methyl)phenyl)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;N-(3-(2-(2-(aminomethyl)phenyl)-7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(4-fluorophenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-phenyl-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(2-(methylsulfonyl)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(4-(dimethylcarbamoyl)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(pyrimidin-5-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(pyridin-3-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(4-(morpholine-4-carbonyl)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(4-(pyrrolidine-1-carbonyl)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(4-(methylsulfonyl)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(6-methoxypyridin-3-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(4-cyanophenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(2-methoxyphenyl)-1H-indole-7-carboxamide;N-(3-(7-carbamoyl-3-(2-cyanoacetamido)-1H-indol-4-yl)-2-methylphenyl)thiazole-2-carboxamide;4-(2-acrylamidophenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(4-(morpholinomethyl)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(4-carbamoylphenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-5-(thiazol-2-ylmethylamino)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide;4-(3-(methylamino)phenyl)-1H-indole-7-carboxamide;4-(3-(N-methylacrylamido)phenyl)-1H-indole-7-carboxamide;4-(2-methyl-3-(2-methylenebutanamido)phenyl)-1H-indole-7-carboxamide;4-(2-methyl-3-(3-(pyrrolidin-1-yl)propanamido)phenyl)-1H-indole-7-carboxamide;4-(3-methacrylamido-2-methylphenyl)-1H-indole-7-carboxamide;(E)-4-(3-(3-cyclopropylacrylamido)-2-methylphenyl)-1H-indole-7-carboxamide;(E)-4-(2-methyl-3-(3-(pyridin-2-yl)acrylamido)phenyl)-1H-indole-7-carboxamide;(E)-4-(2-methyl-3-(3-(1-methyl-1H-pyrazol-4-yl)acrylamido)phenyl)-1H-indole-7-carboxamide;(E)-ethyl4-(3-(7-carbamoyl-1H-indol-4-yl)-2-methylphenylamino)-4-oxobut-2-enoate;(E)-4-(3-(4-(dimethylamino)but-2-enamido)-2-methylphenyl)-1H-indole-7-carboxamide;(E)-4-(2-methyl-3-(3-(pyridin-3-yl)acrylamido)phenyl)-1H-indole-7-carboxamide;(E)-4-(2-methyl-3-(4-methylpent-2-enamido)phenyl)-1H-indole-7-carboxamide;N1-(3-(7-carbamoyl-1H-indol-4-yl)-2-methylphenyl)-N4-ethylmaleamide;4-(3-acetamido-2-methylphenyl)-1H-indole-7-carboxamide;(E)-4-(3-but-2-enamido-2-methylphenyl)-1H-indole-7-carboxamide;4-(2-methyl-3-(3-morpholinopropanamido)phenyl)-1H-indole-7-carboxamide;(E)-4-(2-methyl-3-(3-(thiazol-2-yl)acrylamido)phenyl)-1H-indole-7-carboxamide;4-(2-methyl-3-(2-phenylacrylamido)phenyl)-1H-indole-7-carboxamide;(E)-4-(2-methyl-3-(4-(piperidin-1-yl)but-2-enamido)phenyl)-1H-indole-7-carboxamide;(E)-4-(2-methyl-3-(4-((tetrahydrofuran-2-yl)methylamino)but-2-enamido)phenyl)-1H-indole-7-carboxamide;(E)-4-(3-(4-(2-methoxyethylamino)but-2-enamido)-2-methylphenyl)-1H-indole-7-carboxamide;(E)-4-(3-(4-(cyclopropylamino)but-2-enamido)-2-methylphenyl)-1H-indole-7-carboxamide;(E)-4-(2-methyl-3-(4-morpholinobut-2-enamido)phenyl)-1H-indole-7-carboxamide;(E)-4-(2-methyl-3-(4-(4-methylpiperazin-1-yl)but-2-enamido)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-4-(benzyloxy)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-5-(benzyloxy)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-4-(thiazol-2-ylmethoxy)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-5-(thiazol-2-ylmethoxy)phenyl)-1H-indole-7-carboxamide;4-(2-acrylamido-4-(thiazol-2-ylmethoxy)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;4-(2-acrylamido-4-(benzyloxy)phenyl)-1H-indole-7-carboxamide;4-(5-acrylamidopyridin-3-yl)-1H-indole-7-carboxamide;4-(2-acrylamidopyridin-4-yl)-1H-indole-7-carboxamide;N1-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-N4-(2-methoxyethyl)maleamide;N1-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-N4-ethylmaleamide;4-(3-(1-methyl-1,2,5,6-tetrahydropyridine-3-carboxamido)phenyl)-1H-indole-7-carboxamide;4-(3-(vinylsulfonamido)phenyl)-1H-indole-7-carboxamide;4-(3-(2-oxopropanamido)phenyl)-1H-indole-7-carboxamide; (E)-methyl4-(3-(7-carbamoyl-1H-indol-4-yl)phenylamino)-4-oxobut-2-enoate;4-(3-(cyanomethylcarbamoyl)phenyl)-1H-indole-7-carboxamide;N-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-5-methylisoxazole-4-carboxamide;N1-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-N4-methylfumaramide;N1-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-N4,N4-dimethylfumaramide;N1-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-N4-ethylfumaramide;N1-(3-(7-carbamoyl-1H-indol-4-yl)phenyl)-N4-cyclopropylfumaramide;(E)-4-(3-(7-carbamoyl-1H-indol-4-yl)phenylamino)-4-oxobut-2-enoic acid;4-(3-(N-isobutylacrylamido)phenyl)-1H-indole-7-carboxamide;1-Acryloyl-1,2,3,6-tetrahydro-pyrrolo[2,3-e]indole-5-carboxylic acidamide; 4-acrylamido-1H-indole-7-carboxamide;4-(3-(N-(cyanomethyl)sulfamoyl)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamidophenyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;4-(3-((2-oxopropanamido)methyl)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamidophenyl)-1H-indazole-7-carboxamide;4-(3-acrylamido-2-methoxyphenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-fluorophenyl)-1H-indole-7-carboxamide;4-(5-acrylamido-2-fluorophenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-4-fluorophenyl)-1H-indole-7-carboxamide;4-(5-acrylamido-2-chlorophenyl)-1H-indole-7-carboxamide;4-(5-acrylamido-2,4-difluorophenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-4-cyanophenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2,6-difluorophenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-5-methylphenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-4-methylphenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-4-methoxyphenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-5-methoxyphenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-4-chlorophenyl)-1H-indole-7-carboxamide;4-(5-acrylamido-2,3-difluorophenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-5-cyanophenyl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-cyanophenyl)-1H-indole-7-carboxamide;4-(3-acrylamidophenyl)-2-vinyl-1H-indole-7-carboxamide;4-(3-acrylamidophenyl)-2-ethyl-1H-indole-7-carboxamide;4-(3-(2-(morpholinomethyl)acrylamido)phenyl)-1H-indole-7-carboxamide;4-(3-(2-((dimethylamino)methyl)acrylamido)phenyl)-1H-indole-7-carboxamide;(E)-4-(3-(4-(dimethylamino)but-2-enamido)-2-methylphenyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;4-((1R,3S)-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;4-(cis-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;4-((1S,3S)-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;4-(trans-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;4-(cis-3-acrylamidocyclohexyl)-1H-indole-7-carboxamide;4-(3-(2-(aminomethyl)acrylamido)phenyl)-1H-indole-7-carboxamide;4-((1R,3S)-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;4-(3-(2-((methylamino)methyl)acrylamido)phenyl)-1H-indole-7-carboxamide;4-(3-acrylamidophenyl)-2-methyl-1H-indole-7-carboxamide;4-((1S,3S)-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;4-(3-acrylamidophenyl)-2-(2-ethoxyethyl)-1H-indole-7-carboxamide;4-(3-acrylamidophenyl)-2-(2-hydroxyethyl)-1H-indole-7-carboxamide;4-(1-acryloylpiperidin3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;4-(3-acrylamido-2-methylphenyl)-2-(1-isopropyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;4-(3-(4-cyclopropylbenzamido)-2-methylphenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(2-methyl-3-(1-methylpiperidine-4-carboxamido)phenyl)-2-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-7-carboxamide;4-(3-(N-(cyclopentylmethyl)acrylamido)phenyl)-1H-indole-7-carboxamide;ethyl4-(7-carbamoyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-1H-indol-2-yl)5,6-dihydropyridine-1(2H)-carboxylate;(R)-4-(3-(4-oxoquinazolin-3(4H)-yl)piperidin-1-yl)-1H-indole-7-carbonitrile;4-(2,6-dichlorobenzyl)-2-(p-tolyl)-1H-indole-7-carboxamide;(E)-4-(3-(2-cyano-3-hydroxybut-2-enamido)phenyl)-1H-indole-7-carboxamide;4-(cis-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;4-(trans-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;4-(trans-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)oxy)-1H-indole-7-carboxamide;(S)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide*;(R)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-indole-7-carboxamide*;4-((1-acryloylazetidin-3-yl)(methyl)amino)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;(R)-4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide*;(S)-4-(1-acryloylpiperidin-3-yl)-1H-indole-7-carboxamide*;(S)-4-(1-acryloylpiperidin-3-yl)-2-methyl-1H-indole-7-carboxamide;(R)-4-(1-acryloylpiperidin-3-yl)-2-methyl-1H-indole-7-carboxamide;(R)-4-(4-acryloylmorpholin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;(S)-4-(4-acryloylmorpholin-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;(R)-4-(1-acryloylpyrrolidin-3-yl)-2-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-1H-indole-7-carboxamide;2-methyl-4-(methyl(1-propioloylazetidin-3-yl)amino)-1H-indole-7-carboxamide;(S)-4-(1-acryloylpyrrolidin-3-yl)-2-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-1H-indole-7-carboxamide;(R)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;(S)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;(R)-4-(1-acryloylpiperidin-3-yl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;(S)-4-(1-acryloylpiperidin-3-yl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;(R)-7-(1-acryloylpiperidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridine-4-carboxamide;(S)-7-(1-acryloylpiperidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-c]pyridine-4-carboxamide;(S)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-indole-7-carboxamide;4-((3S,5R)-1-acryloyl-5-(hydroxymethyl)piperidin-3-yl)-1H-indole-7-carboxamide;4-((3S,5S)-1-acryloyl-5-(hydroxymethyl)piperidin-3-yl)-1H-indole-7-carboxamide;4-((3R,5S)-1-acryloyl-5-(hydroxymethyl)piperidin-3-yl)-1H-indole-7-carboxamide;4-((3R,5R)-1-acryloyl-5-(hydroxymethyl)piperidin-3-yl)-1H-indole-7-carboxamide;(R)-4-(1-acryloylpyrrolidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;(S)-4-(1-acryloylpyrrolidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;4-((1R,3R)-3-acrylamidocyclopentyl)-1H-indole-7-carboxamide;(S)-4-(1-acryloylpiperidin-3-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;(R)-4-(1-acryloylpiperidin-3-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;(R)-2-methyl-4-(1-propionylpyrrolidin-3-yl)-1H-indole-7-carboxamide;(S)-2-methyl-4-(1-propionylpyrrolidin-3-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(isochroman-7-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(4,4-difluorocyclohex-1-en-1-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(4-(methylsulfonyl)cyclohex-1-en-1-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(6-morpholinopyridin-3-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(chroman-7-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(5-(morpholinomethyl)pyridin-2-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1-methyl-1H-pyrazol-5-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(1-propylpiperidin-4-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(tetrahydrofuran-3-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(3-hydroxyoxetan-3-yl)-1H-indole-7-carboxamide;4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-methyl-1H-indole-7-carboxamide;(R)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-indole-7-carboxamide;(S)-4-(1-acryloylpyrrolidin-3-yl)-2-methyl-1H-indole-7-carboxamide*;(R)-4-(1-acryloylpyrrolidin-3-yl)-2-methyl-1H-indole-7-carboxamide*;4-((1R,5S)-6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-1H-indole-7-carboxamide;4-((1S,5R)-6-acryloyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-1H-indole-7-carboxamide;(R)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;(S)-4-(1-(1-acryloylazetidin-3-yl)ethyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamide;4-((1-acryloylazetidin-3-yl)amino)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;4-((1-acryloyl-3-methylazetidin-3-yl)(methyl)amino)-1H-indole-7-carboxamide;4-((1-cyanoazetidin-3-yl)(methyl)amino)-2-methyl-1H-indole-7-carboxamide;4-(2-chloro-6-fluorobenzyl)-2-p-tolyl-1H-indole-7-carboxamide;(S)-4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(tetrahydrofuran-3-yl)-1H-indole-7-carboxamide;(R)-4-((1-acryloylazetidin-3-yl)(methyl)amino)-2-(tetrahydrofuran-3-yl)-1H-indole-7-carboxamide;(S)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;(R)-4-(4-acryloyl-1,4-oxazepan-6-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide;(S)-4-(1-acryloylpiperidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide;or(R)-4-(1-acryloylpiperidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-7-carboxamide.21. A method of treating a disease comprising administering atherapeutically effective amount of a compound of claim 1 to a patientin need thereof.
 22. The method according to claim 21, wherein thedisease is rheumatoid arthritis, juvenile rheumatoid arthritis,osteoarthritis, Crohn's disease, inflammatory bowel disease, ulcerativecolitis, psoriatic arthritis, psoriasis, ankylosing spondylitis,interstitial cystitis, asthma, systemic lupus erythematosus, lupusnephritis, B cell chronic lymphocytic lymphoma, multiple sclerosis,chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle celllymphoma, B-cell non-Hodgkin's lymphoma, activated B-cell like diffuselarge B-cell lymphoma, multiple myeloma, diffuse large B-cell lymphoma,follicular lymphoma, hairy cell leukemia or Lymphoblastic lymphoma. 23.A kit comprising a packaged product comprising components with which toadminister a compound of claim 1 for treatment of an autoimmunedisorder.
 24. The kit according to claim 23, wherein the packagedproduct comprises a compound of Formula (I) and instructions for use.25. A pharmaceutical composition comprising a compound according toclaim 1 and one or more pharmaceutically acceptable excipients.